Heterocyclic amides exhibiting and inhibitory activity at the vanilloid receptor 1(vr1)

ABSTRACT

Compounds of formula I,  
                 
 
wherein R 1 , n, R 3 , R 4 , R 7 , R 8  and P are as defined in the specification, salts, solvates or solvated salts thereof, processes for their preparation, new intermediates used in the preparation thereof, pharmaceutical compositions containing said compounds and the use of said compounds in therapy.

FIELD OF THE INVENTION

The present invention relates to new compounds, to pharmaceuticalcompositions containing said compounds and to the use of said compoundsin therapy. The present invention further relates to processes for thepreparation of said compounds and to new intermediates used in thepreparation thereof.

BACKGROUND OF THE INVENTION

Pain sensation in mammals is due to the activation of the peripheralterminals of a specialized population of sensory neurons known asnociceptors. Capsaicin, the active ingredient in hot peppers, producessustained activation of nociceptors and also produces a dose-dependentpain sensation in humans. Cloning of the vanilloid receptor 1 (VR1 orTRPV1) demonstrated that VR1 is the molecular target for capsaicin andits analogues. (Caterina, M. J., Schumacher, M. A., et. al. Nature(1997) v. 389 p 816-824). Functional studies using VR1 indicate that itis also activated by noxious heat, tissue acidification) and otherinflammatory mediators (Tominaga, M., Caterina, M. J. et. al. Neuron(1998) v. 21, p. 531-543). Expression of VR1 is also regulated afterperipheral nerve damage of the type that leads to neuropathic pain.These properties of VR1 make it a highly relevant target for pain andfor diseases involving inflammation. While agonists of the VR1 receptorcan act as analgesics through nociceptor destruction, the use ofagonists, such as capsaicin and its analogues, is limited due to theirpungency, neurotoxicity and induction of hypothermia. Instead, agentsthat block the activity of VR1 should prove more useful. Antagonistswould maintain the analgesic properties, but avoid pungency andneurotoxicity side effects. Compounds with VR1 inhibitor activity arebelieved to be of potential use for the treatment and/or prophylaxis ofdisorders such as pain, especially that of inflammatory or traumaticorigin such as arthritis, ischaemia, cancer, fibromyalgia, low back painand post-operative pain (Walker et al J Pharmacol Exp Ther. January2003;304(1):56-62). In addition to this visceral pains such as chronicpelvic pain, cystitis, irritable bowel syndrome (IBS), pancreatitis andthe like, as well as neuropathic pain such as sciatia, diabeticneuropathy, HIV neuropathy, multiple sclerosis, and the like (Walker etal ibid, Rashid et al J Pharmacol Exp Ther. March 2003;304(3):940-8),are potential pain states that could be treated with VR1 inhibiton Thesecompounds are also believed to be potentially useful for inflammatorydisorders like asthma, cough, inflammatory bowel disease (IBD) (Hwangand Oh Curr Opin Pharmacol June 2002;2(3):235-42). Compounds with VR1blocker activity are also useful for itch and skin diseases likepsoriasis and for gastro-esophageal reflux disease (GERD), emesis,cancer, urinary incontinence and hyperactive bladder (Yiangou et al BJUInt June 2001;87(9):774-9, Szallasi Am J Clin Pathol (2002) 118:110-21). VR1 inhibitors are also of potential use for the treatmentand/or prophylaxis of the effects of exposure to VR1 activators likecapsaicin or tear gas, acids or heat (Szallasi ibid).

A further portential use relates to the treatment of tolerance to VR1activators. VR1 inhibitors may also be useful in the treatment ofinterstitial cystitis and pain related to interstitial cystitis.

DETAILED DESCRIPTION OF THE INVENTION

The object of the present invention is to provide compounds exhibitingan inhibitory activity at the vanilloid receptor 1 (VR1).

The present invention provides a compound of formula I

wherein:

ring P is C₆₋₁₀aryl, C₃₋₇cycloalkyl, C₅₋₆heteroaryl, which ring P may befused with phenyl, C₅₋₆heteroaryl, C₃₋₇cycloalkyl orC₃₋₇heterocycloalkyl;

R¹ is NO₂, NH₂, halo, N(C₁₋₆alkyl)₂, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₆haloalkyl, C₁₋₆haloalkylO, phenylC₀₋₆alkyl,C₅₋₆heteroarylC₀₋₆alkyl, C₃₋₇cycloalkylC₀₋₆alkyl,C₃₋₇heterocycloalkylC₀₋₆alkyl, C₁₋₆alkylOC₀₋₆alkyl, C₁₋₆alkylSC₀₋₆alkylor C₁₋₆alkylNC₀₋₆alkyl;

n is 1, 2, 3, 4 or 5;

X is O or S, when

R³ is H, C₁₋₆alkyl, C₁₋₆haloalkyl, R⁵OC₁₋₆alkyl, R⁵OCO, R⁵CO, NR⁵R⁶CO,NR⁵R⁶C₀₋₆alkyl, C₂₋₆alkenylOC₀₋₆alkyl or hydroxyC₁₋₆alkyl; and

R⁴ is nil; or

X is N, when

R³ is H, C₁₋₆alkyl, C₁₋₆iodoalkyl, C₁₋₆bromoalkyl, C₁₋₆chloroalkyl,C₁₋₆alkylOC₀₋₆alkyl, R⁵OC₁₋₆alkyl, R⁵CO, R⁵CO2, NR⁵R⁶CO, NR⁵R⁶C₀₋₆alkylor C₂₋₆alkenylOC₀₋₆alkyl; and

R⁴ is H, C₁₋₄alkyl, hydroxyC₁₋₆alkyl or C₁₋₆alkylOC₁₋₆alkyl; or

X is N, when R³ is C₁₋₆fluoroalkyl or hydroxyC₁₋₂alkyl and R⁴ is H;

R⁵ and R⁶ are independently selected from H, C₁₋₆alkyl, C₆₋₁₀aryl,C₅₋₆heteroaryl, C₁₋₄alkylSO₂ and C₁₋₃ alkylCO;

R⁷ and R⁸ are independently selected from H, C₁₋₆alkyl, halo, cyano,C₁₋₆alkylOC₀₋₆alkyl, OH, NO₂ and COR⁹, N(R⁹)₂;

R⁹ is H or C₁₋₆alkyl;

and wherein any alkyl, alkylOalkyl, haloalkyl, haloalkylO, phenyl,heteroaryl, cycloalkyl or heterocycloalkyl group may be substituted withone or more A; and

A is OH, NO₂, C₁₋₆alkylCO, C₁₋₆alkylO(CO), N(R⁹)₂, R⁹S, R⁹SO₂, halo orC₁₋₆alkylOC₀₋₆alkyl,

or salts, solvates or solvated salts thereof.

One embodiment of the invention relates to the compound of formula Iwherein ring P is C₆₋₁₀aryl, C₅₋₆heteroaryl, which ring P may be fusedwith C₃₋₇heterocycloalkyl;

R¹ is NO₂, NH₂, halo, N(C₁₋₆alkyl)₂, C₁₋₆alkyl, C₂₋₆alkenyl,C₁₋₆haloalkyl, C₁₋₆haloalkylO, phenylC₀₋₆alkyl,C₃₋₇heterocycloalkylC₀₋₆alkyl, C₁₋₆alkylOC₀₋₆alkyl orC₁₋₆alkylSC₀₋₆alkyl;

n is 1, 2 or 3;

X is O or S, when

R³ is C₁₋₆alkyl, NR⁵R⁶CO, NR⁵R⁶C₀₋₆alkyl, C₂₋₆alkenylOC₀₋₆alkyl orhydroxyC₁₋₆alkyl; and

R⁴ is nil; or

X is N, when

R³ is H or C₁₋₆alkyl; and

R⁴ is C₁₋₄alkyl or hydroxyC₁₋₆alkyl; or

X is N, when R³ is C₁₋₆fluoroalkyl and R⁴is H;

R⁵ and R⁶ are independently selected from H, C₆₋₁₀aryl, C₅₋₆heteroaryl,C₁₋₄alkylSO₂ and C₁₋₃ alkylCO;

R⁷ and R⁸ are independently selected from H, halo and cyano;

and wherein any alkyl, phenyl, heteroaryl group may be substituted withone or more A; and

A is OH, NO₂, halo or C₁₋₄alkylOC₀₋₆alkyl;

or salts, solvates or solvated salts thereof.

In one embodiment of the invention X is S and R³is C₁₋₆alkyl, NR⁵R⁶CO,NR⁵R⁶C₀₋₆alkyl, C₂₋₆alkenylOC₀₋₆alkyl or hydroxyC₁₋₆alkyl.

In another embodiment X is S and R³is methyl.

In a further embodiment X is S and R³is hydroxymethyl.

In one embodiment of the invention X is O and R³ is C₁₋₆alkyl orhydroxyC₁₋₆alkyl.

In another embodiment X is O and R³ is methyl.

In a further embodiment X is O and R³ is hydroxymethyl.

In one embodiment of the invention X is N and R³ is C₁₋₆alkyl and R⁴ isC₁₋₆alkyl or hydroxyC₁₋₆alkyl.

In another embodiment R³ is methyl and R⁴is methyl or 2-hydroxyethyl.

In a further embodiment X is N and R³ is trifluoromethyl and R⁴is H

R⁵ and R⁶ may optionally be substituted by A. In one embodiment R⁵ andR⁶ are selected independently from the group consisting of H,methylsulfonyl, acetyl and substituted or unsubstituted heteroaryl suchas pyrazole or pyridine.

One embodiment of the invention relates to the compound of formula Iwherein R³ is hydroxymethyl, allyloxymethyl, ethoxymethyl,methoxypyridinylaminomethyl, pyrazolylaminomethyl, aminomethyl,methylsulfonylaminomethyl, acetylaminomethyl, carboxamide, methyl,hydroxyethyl, nitrophenylaminomethyl, hydroxycarbonyl ormethoxycarbonyl.

R⁴ may be selected from the group consisting of H, C₀₋₄alkyl orhydroxyC₁₋₆alkyl.

In one embodiment of the invention P is substituted with 0, 1, 2, 3 or 4groups R¹, wherein the number of R¹ substituents on the P ring isdesignated by the term n. In another embodiment of the invention n is 1or 2.

Another embodiment of the invention relates to the compound of formula Iwherein ring P is phenyl.

In a further embodiment ring P is phenyl and R¹ is NO₂, NH₂, halo,N(C₁₋₆alkyl)₂, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,C₁₋₆haloalkylO, phenylC₀₋₆alkyl, C₅₋₆heteroarylC₀₋₆alkyl,C₃₋₇cycloalkylC₀₋₆alkyl, C₃₋₇heterocycloalkylC₀₋₆alkyl,C₁₋₆alkylOC₀₋₆alkyl, C₁₋₆alkylSC₀₋₆alkyl or C₁₋₆alkylNC₀₋₆alkyloptionally substituted with one or more A.

In yet another embodiment ring P is pyrazolyl, pyridine, benzdioxolane,furan, thiophene or naphthalene and R¹ is NO₂, NH₂, halo, N(C₁₋₆alkyl)₂,C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, C₁₋₆haloalkylO,phenylC₀₋₆alkyl, C₅₋₆heteroarylC₀₋₆alkyl, C₃₋₇cycloalkylC₀₋₆alkyl,C₃₋₇heterocycloalkylC₀₋₆alkyl, C₁₋₆alkylOC₀₋₆alkyl, C₁₋₆alkylSC₀₋₆alkylor C₁₋₆alkylNC₀₋₆alkyl optionally substituted with one or more A.

Ring P may be substituted by R¹ on a nitrogen or carbon atom in ring P.Further, one atom on ring P may be substituted by two substituents R¹.

Any alkyl, alkylOalkyl, haloalkyl, haloalkylO, phenyl, heteroaryl,cycloalkyl or heterocycloalkyl group present in the substituents of thecompounds of formula I may be substituted with one or more A. Oneembodiment of the invention relates to compounds of formula I wherein Ais selected from the group consisting of OH, NO₂, halo orC₁₋₆alkylOC₀₋₆alkyl.

Another embodiment of the invention relates to compounds selected fromthe group consisting of

3-Fluoro-N-(2-methyl-1,3-benzothiazol-5-yl)-4-trifluoromethyl-benzamide,

2-tert-Butyl-5-methyl-2H-pyrazole-3-carboxylic acid(2-methyl-1,3-benzothiazol-5-yl)-amide,

2-Fluoro-N-(2-methyl-1,3-benzothiazol-5-yl)-4-trifluoromethyl-benzamide,

2-Fluoro-N-(2-methyl-1,3-benzothiazol-5-yl)-3-trifluoromethyl-benzamide,

4-Fluoro-N-(2-methyl-1,3-benzothiazol-5-yl)-3-trifluoromethyl-benzamide,

3,4-Dimethyl-N-(2-methyl-benzothiazol-5-yl)-benzamide,

2,2-Difluoro-benzo[1,3]dioxole-5-carboxylic acid(2-methyl-1,3-benzothiazol-5-yl)-amide,

N-(2-Methyl-1,3-benzothiazol-5-yl)-6-trifluoromethyl-nicotinamide,

N-(2-Methyl-1,3-benzothiazol-5-yl)-4-propyl-benzamide,

3-Iodo-N-(2-methyl-1,3-benzothiazol-5-yl)-benzamide,

2,5-Dimethyl-furan-3-carboxylic acid(2-methyl-1,3-benzothiazol-5-yl)-amide,

5-tert-Butyl-2-methyl-furan-3-carboxylic acid(2-methyl-1,3-benzothiazol-5-yl)-amide,

4-Bromo-3-methyl-N-(2-methyl-1,3-benzothiazol-5-yl)-benzamide,

3,4-Difluoro-N-(2-methyl-1,3-benzothiazol-5-yl)-benzamide,

3-Chloro-2-fluoro-N-(2-methyl-1,3-benzothiazol-5-yl)-benzamide,

Pyridine-2-carboxylic acid (2-methyl-1,3-benzothiazol-5-yl)-amide,

2-Benzyl-5-tert-butyl-2H-pyrazole-3-carboxylic acid(2-methyl-1,3-benzothiazol-5-yl)-amide,

3-Fluoro-4-trifluoromethyl-N-(2-trifluoromethyl-1H-benzimidazol-5-yl)-benzamide,

2-Fluoro-5-trifluoromethyl-N-(2-trifluoromethyl-1H-benzimidazol-5-yl)-benzamide,

4-Chloro-N-(2-methyl-1,3-benzothiazol-5-yl)-benzamide,

1-Phenyl-5-trifluoromethyl-1H-pyrazole-3-carboxylic acid(2-methyl-1,3-benzothiazol-5-yl)-amide,

1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid(2-methyl-1,3-benzothiazol-5-yl)-amide,

2,3-Difluoro-N-(2-methyl-1,3-benzothiazol-5-yl)-4-trifluoromethyl-benzamide,

3-Fluoro-4-methyl-N-(2-methyl-1,3-benzothiazol-5-yl)-benzamide,

4-tert-Butyl-N-(2-methyl-1,3-benzothiazol-5-yl)-benzamide,

4-Ethyl-N-(2-methyl-1,3-benzothiazol-5-yl)-benzamide,

4-tert-Butyl-N-(2-methyl-benzooxazol-5-yl)-benzamide,

Biphenyl-4-carboxylic acid (2-methyl-1,3-benzothiazol-5-yl)-amide,

3-Bromo-thiophene-2-carboxylic acid(2-methyl-1,3-benzothiazol-5-yl)-amide,

4-Bromo-2-methyl-N-(2-methyl-1,3-benzothiazol-5-yl)-benzamide,

4-tert-Butoxy-N-(2-methyl-1,3-benzothiazol-5-yl)-benzamide,

2-Chloro-3,4-dimethoxy-N-(2-methyl-1,3-benzothiazol-5-yl)-benzamide,

4-Iodo-N-(2-methyl-1,3-benzothiazol-5-yl)-benzamide,

4-Amino-N-(2-methyl-1,3-benzothiazol-5-yl)-3-nitro-benzamide,

N-(2-Methyl-1,3-benzothiazol-5-yl)-4-vinyl-benzamide,

4-Ethoxy-N-(2-methyl-1,3-benzothiazol-5-yl)-benzamide,

4-Ethylsulfanyl-N-(2-methyl-1,3-benzothiazol-5-yl)-benzamide,

4-Dimethylamino-naphthalene-1-carboxylic acid(2-methyl-1,3-benzothiazol-5-yl)-amide,

2-Fluoro-6-iodo-N-(2-methyl-1,3-benzothiazol-5-yl)-benzamide,

4-Ethoxymethyl-N-(2-methyl-1,3-benzothiazol-5-yl)-benzamide,

N-(2-Methyl-1,3-benzothiazol-5-yl)-4-trifluoromethoxy-benzamide, and

4-Chloro-3-fluoro-N-(2-methyl-1,3-benzothiazol-5-yl)-benzamide,

or salts, solvates or solvated salts thereof.

A further embodiment of the invention relates to compounds selected fromthe group consisting of

4-tert-Butyl-N-(2-formyl-1,3-benzothiazol-5-yl)-benzamide,

4-tert-Butyl-N-(2-hydroxymethyl- 1,3-benzothiazol-5-yl)-benzamide,

5-(4-tert-butylbenzoylamino)-1,3-benzothiazol-2-ylcarboxylic acid, and

4-tert-Butyl-N-(2-methoxycarbonyl-1,3-benzothiazol-5-yl)-benzamide,

or salts, solvates or solvated salts thereof.

Yet another embodiment of the invention relates to compounds selectedfrom the group consisting of

4-tert-Butoxy-N-[2-(hydroxymethyl)-1,3-benzothiazol-5-yl]benzamide,

5 4-Bromo-N-[2-(hydroxymethyl)-1,3-benzothiazol-5-yl]benzamide,

N-[2-(Hydroxymethyl)-1,3-benzothiazol-5-yl]4-iodobenzamide,

N-[2-(Hydroxymethyl)-1,3-benzothiazol-5-yl]-4-morpholin4-ylbenzamide,

N-{2-[(Allyloxy)methyl]-1,3-benzothiazol-5-yl}-4-morpholin4-ylbenzamide,

N-[2-(Hydroxymethyl)-1,3-benzothiazol-5-yl]-1-phenyl-5-propyl-1H-pyrazole4-carboxamide,

1-tert-Butyl-N-[2-(hydroxymethyl)-1,3-benzothiazol-5-yl]-3-methyl-1H-pyrazole-5-carboxamide,

4-(Ethoxymethyl)-N-[2-(hydroxymethyl)-1,3-benzothiazol-5-yl]benzamide,

N-[2-(Hydroxymethyl)-1,3-benzothiazol-5-yl]-1-phenyl-1H-pyrazole-5-carboxamide,

4-Bromo-N-[2-(hydroxymethyl)-1,3-benzothiazol-5-yl]-2-methylbenzamide,

4-tert-Butoxy-N-(2-methyl-1,3-benzoxazol-5-yl) benzamide,

N-(4-Bromo-2-methyl-1,3-benzothiazol-5-yl)-4-tert-butylbenzamide,

4-tert-Butyl-N-(4,7-dibromo-2-methyl-1,3-benzothiazol-5-yl)benzamide,

N-[2-(hydroxymethyl)-1,3-benzothiazol-5-yl]-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide,

4-Iodo-N-(2-methyl-5-benzothiazolyl)benzamide,

4-(tert-Butoxymethyl)-N-[2-(hydroxymethyl)-1,3-benzothiazol-5-yl]benzamide,

N-(1,2-Dimethyl-1H-benzimidazol-5-yl)4-iodobenzamide,

4-tert-Butyl-N-(2-{[(2-methoxypyridin-3-yl)amino]methyl}-1,3-benzothiazol-5-yl)benzamide,

4-tert-Butyl-N-[2-(1-hydroxyethyl)-1,3-benzothiazol-5-yl)benzamide,

4-tert-Butyl-N-(2-((1H-pyrazol-3-ylamino)methyl]-1,3-benzothiazol-5-yl}benzamide,

4-(1,1-Dimethylethyl)-N-[2-[[(4-nitrophenyl)amino]methyl]-5-benzothiazolyl]-benzamide,

N-[2-(Aminomethyl)-1,3-benzothiazol-5-yl]-4-tert-butylbenzamide,

4-tert-Butyl-N-(2-{[(methylsulfonyl)amino]methyl}-1,3-benzothiazol-5-yl)benzamide,

N-{2-[(Acetylamino)methyl]-1,3-benzothiazol-5-yl1-4-tert-butylbenzamide,

5-[(4-tert-Butylbenzoyl)amino]-1,3-benzothiazole-2-carboxamide,

N-1,3-Benzothiazol-5-yl-4-tert-butylbenzamide,

4-Chloro-N-[2-(hydroxymethyl)-1,3-benzothiazol-5-yl]benzamide,

1-(4-chlorophenyl)-N-[2-(hydroxymethyl)-1,3-benzothiazol-5-yl]-5-propyl-1H-pyrazole4-carboxamide,

1-(4-chlorophenyl)-N-[2-(hydroxymethyl)-1,3-benzothiazol-5-yl]-5-(trifluoromethyl)-1H-pyrazole4-carboxamide,

N-(2,4-dimethyl-1,3-benzothiazol-5-yl)4-(1-hydroxy-1-methylethyl)benzamide,

4-(Hydroxymethyl)-N-[2-(hydroxymethyl)-1,3-benzothiazol-5-yl]benzamid,eand

4-tert-butyl-N-(4-cyano-2-methyl-1,3-benzothiazol-5-yl)benzamide,

or salts, solvates or solvated salts thereof.

One embodiment of the invention relates to compounds selected from thegroup consisting of

N-[2-(Hydroxymethyl)-1,3-benzothiazol-5-yl]4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzamide,

N-[2-(Hydroxymethyl)-1,3-benzothiazol-5-yl]4-isopropoxybenzamide,

4-Bromo-2-chloro-N-[2-(hydroxymethyl)-1,3-benzothiazol-5-yl]benzamide,

4-Bromo-2-fluoro-N-[2-(hydroxymethyl)-1,3-benzothiazol-5-yl]benzamide,

N-[2-(Hydroxymethyl)-1,3-benzothiazol-5-yl]-4-(morpholin-4-ylmethyl)benzamide,

3-Fluoro-N-[2-(hydroxymethyl)-1,3-benzothiazol-5-yl]4-(trifluoromethyl)benzamide,

4-tert-butoxy-N-[4-chloro-2-(hydroxymethyl)-1,3-benzothiazol-5-yl]benzamide,

4-(tert-Butoxymethyl)-N-[4-chloro-2-(hydroxymethyl)-1,3-benzothiazol-5-yl]benzamide,and

4-tert-butyl-N-[2-(hydroxymethyl)-1,3-benzoxazol-5-yl]benzamide,

or salts, solvates or solvated salts thereof.

Listed below are definitions of various terms used in the specificationand claims to describe the present invention.

For the avoidance of doubt it is to be understood that where in thisspecification a group is qualified by ‘hereinbefore defined’, ‘definedhereinbefore’ or ‘defined above’ the said group encompasses the firstoccurring and broadest definition as well as each and all of the otherdefinitions for that group.

For the avoidance of doubt it is to be understood that in thisspecification ‘C₁₋₆’ means a carbon group having 1, 2, 3, 4, 5 or 6carbon atoms.

In this specification, unless stated otherwise, the term “alkyl”includes both straight and branched chain alkyl groups and may be, butare not limited to methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,s-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, neo-pentyl, n-hexyl ori-hexyl, t-hexyl. The term C₁₋₃ alkyl having 1 to 3 carbon atoms and maybe methyl, ethyl, n-propyl, i-propyl or tert-butyl.

The term ‘C₀’ means a bond or does not excist. For example when R⁴ isC₀alkyl, R⁴ does not excist and “arylC₀alkyl” is equivalent with “aryl”,“C₂aklylOC₀alkyl” is equivalent with “C₂alkylO”.

In this specification, unless stated otherwise, the term “alkenyl”includes both straight and branched chain alkenyl groups. The term“C₂₋₆alkenyl” having 2 to 6 carbon atoms and one or two double bonds,may be, but is not limited to vinyl, allyl, propenyl, butenyl, crotyl,pentenyl, or hexenyl, and a butenyl group may for example be buten-2-yl,buten-3-yl or buten-4-yl.

In this specification, unless stated otherwise, the term “alkynyl”includes both straight and branched chain alkynyl groups. The term“C₂₋₆alkynyl” having 2 to 6 carbon atoms and one or two trippel bonds,may be, but is not limited to etynyl, propargyl, pentynyl or hexynyl anda butynyl group may for example be butyn-3-yl or butyn-4-yl.

In this specification, unless stated otherwise, the term “cycloalkyl”refers to an optionally substituted, saturated cyclic hydrocarbon ringsystem. The term “C₃₋₇cycloalkyl” may be cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl or cycloheptyl.

The term “heterocycloalkyl” denotes a 3- to 7-membered, non-aromatic,partially or completely saturated hydrocarbon group, which contains onering and at least one heteroatom. Examples of said heterocycle include,but are not limited to pyridyl, pyrrolyl, furyl, thienyl, imidazolyl,oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, benzofuryl, indolyl,isoindolyl, benzimidazolyl, pyridazinyl, pyrimidinyl, pyrazinyl,tetrazolyl, triazolyl, pyrrolidinyl, pyrrolidonyl, piperidinyl,piperazinyl, morpholinyl, oxazolyl, 2-oxazolidonyl or tetrahydrofuranyl.

In this specification, unless stated otherwise, the term “aryl” refer toan optionally substituted monocyclic or bicyclic hydrocarbon unsaturatedaromatic ring system. Examples of “aryl” may be, but are not limited tophenyl and naphthyl.

In this specification, unless stated otherwise, the term “heteroaryl”refer to an optionally substituted monocyclic or bicyclic unsaturatedaromatic ring system containing at least one heteroatom selectedindependently form N, O or S. Examples of “heteroaryl” may be, but arenot limited to pyridyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl,isoxazolyl, thiazolyl, pyrazolyl, benzofuryl, indolyl, isoindolyl,benzimidazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, tetrazolyl,triazolyl and oxazolyl.

In this specification, unless stated otherwise, the term “arylalkyl” and“heteroarylalkyl” refer to a substituent that is attached via the alkylgroup to an aryl or heteroaryl group.

In this specification, unless stated otherwise, the term “halo” and“halogen” may be fluoro, iodo, chloro or bromo.

In this specification, unless stated otherwise, the term “haloalkyl”means an alkyl group as defined above, which is substituted with halo asdefined above. The term “C₁₋₆haloalkyl” may include, but is not limitedto fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl,difluoroethyl or bromopropyl. The term “C₁₋₆haloalkylO” may include, butis not limited to fluoromethoxy, difluoromethoxy, trifluoromethoxy,fluoroethoxy or difluoroethoxy.

The present invention relates to the compounds of formula I ashereinbefore defined as well as to the salts, solvates or solvated saltsthereof. Salts for use in pharmaceutical compositions will bepharmaceutically acceptable salts, but other salts may be useful in theproduction of the compounds of formula I.

A suitable pharmaceutically acceptable salt of the compounds of theinvention is, for example, an acid-addition salt, for example aninorganic or organic acid. In addition, a suitable pharmaceuticallyacceptable salt of the compounds of the invention is an alkali metalsalt, an alkaline earth metal salt or a salt with an organic base.

Other pharmaceutically acceptable salts and methods of preparing thesesalts may be found in, for example, Remington's Pharmaceutical Sciences(18^(th) Edition, Mack Publishing Co.).

Some compounds of formula I may have chiral centres and/or geometricisomeric centres (E- and Z- isomers), and it is to be understood thatthe invention encompasses all such optical, diastereoisomeric andgeometric isomers.

The invention also relates to any and all tautomeric forms of thecompounds of formula I.

Methods of Preparation

Another aspect of the present invention provides processes for preparingcompounds of formula I, or salts, solvates or solvated salts thereof.

Throughout the following description of such processes it is to beunderstood that, where appropriate, suitable protecting groups will beadded to, and subsequently removed from, the various reactants andintermediates in a manner that will be readily understood by one skilledin the art of organic synthesis. Conventional procedures for using suchprotecting groups as well as examples of suitable protecting groups aredescribed, for example, in “Protective Groups in Organic Synthesis”, T.W. Green, P. G. M. Wuts, Wiley-Interscience, New York, (1999).References and descriptions of other suitable reactions are described intextbooks of organic chemistry, for example, “Advanced OrganicChemistry”, March, 4^(th) ed. McGraw Hill (1992) or, “OrganicSynthesis”, Smith, McGraw Hill, (1994). For representative examples ofheterocyclic chemistry see for example “Heterocyclic Chemistry”, J. A.Joule, K. Mills, G. F. Smith, 3^(rd) ed. Chapman and Hall (1995), p.189-224 and “Heterocyclic Chemistry”, T. L. Gilchrist, 2^(nd) ed.Longman Scientific and Technical (1992), p. 248-282.

The term “room temperature” and “ambient temperature” shall mean, unlessotherwise specified, a temperature between 16 and 25° C.

One embodiment of the invention relates to processes for the preparationof the compound of formula I, wherein R¹ to R⁸, unless otherwisespecified, are defined as in formula I, comprising;

a) reaction of an aromatic amine of formula (II) with a properlysubstituted acyl chloride (III) optionally in the presence of a base:

This reaction may be performed in any manner known to the skilled personin the art. Suitable solvents to be used for this reaction may behalogenated hydrocarbons such as chloroform, dichloromethane anddichloroethane or aromatic and heteroaromatic compounds such as benzene,toluene, xylene, pyridine and lutidine or ethers such as ethyl ether,tetrahydrofuran and dioxan or any mixtures thereof. Catalysts such asheteroaromatic bases like pyridine and lutidine or tertiary amines liketriethylamine, N-methylmorpholine and ethyl diisopropylamine or polymerbound tertiary amines like N,N-(diisopropyl)aminomethylpolystyrene resinmay be used as well. The temperature may be between 40 and 40° C. andthe reaction time may be between 0.5 and 30 h.

b) reaction of an aromatic amine of formula (II) with a properlysubstituted acid (IV) in the presence of a coupling agent (activator)like for example 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride.

Suitable solvents to be used for this reaction may be tertiary amidessuch as dimethylformamide and dimethylacetamide, halogenatedhydrocarbons such as chloroform, dichloromethane and dichloroethane oraromatic and heteroaromatic compounds such as benzene, toluene, xylene,pyridine and lutidine or ethers such as ethyl ether, tetrahydrofuran anddioxan or any mixtures thereof. Catalysts such as heteroaromatic baseslike pyridine and lutidine or tertiary amines like triethylamine,N-methylmorpholine and ethyl diisopropylamine may be used as well. Thetemperature may be between 10 and 60° C. and the reaction time may bebetween 3 and 30 h.

c) reaction of an hydroxymethyl derivative Ia with methanesulfonylchloride followed by treatment with ammonia.

The mesylation step is carried out using halogenated hydrocarbons suchas chloroform, dichloromethane and dichloroethane as a solvent and atertiary amine like triethylamine, N-methylmorpholine and ethyldiisopropylamine as a base in a temperature range between -20 and 30° C.The amination step step is carried out using a solution of ammonia in analcohol like ethanol or in an aprotic solvent like dioxane or in water.

d) reaction of an aminomethyl derivative Ib with an acyl chloride or asulfonyl chloride

The reaction conditions are similar to the ones described for themesylation step in part c).

e) oxidation of the aldehyde Ic to the corresponding carbonic acid Id

For the oxidation purpose a mixture of sodium chlorite and sulfamic acidin water may be employed

f) decarboxylation of the carbonic acid Id

g) esterification of the carbonic acid Id

h) amidation of the carbonic acid Id

i) reduction of the aldehyde Ic to a corresponding primary alcohol

As a suitable reductive agent sodium borohydride may be used in asolvent like methanol or another alcohol or its mixture with water in atemperature range between -10 and 40° C.

j) treatment of the aldehyde Ic with organometallic reagent leading tosecondary alcohols

Organometalic reagent may be a magnesium derivatives likemethylmagnesium bromide or organolithium compound like methyllithium anda suitable solvent may be chosen from a range of aprotic inert solventslike diethyl ether, tetrahydrofuran, benzene, etc.

k) reductive amination of the aldehyde Ic

Y is aryl, heteroaryl in process i) any primary amine may be usedtogether with an appropriate reductive agent for example decaborane orsodium cyanoborohydride. Both protic and aprotic solvents, for example,alcohols, water, terahydrofuran and mixtures thereof are suitable andthe temperature range is between 0 and 40° C.

l) reduction of the aldehyde Ie to a corresponding primary alcohol as inpart i)

m) treatment of the methyl ester If with organometallic reagent leadingto tertiary alcohols in a similar way to the process described in partj)

n) reaction of the bromo derivative Ig with a cyanation reagent

As a cyanation reagent copper (I) cyanide may be used in an aproticpolar solvent having high boiling point, like dimethyl formamide, atelevated temperature in a range between 150 and 270° C.

o) oxidation of the 2-methyl derivative Ih and subsequent reduction ofthe intermediary aldehyde to the 2-hydroxymethyl derivative Ii

The oxidation step is accomplished by using an appropriate oxidativereagent for example, magnesium dioxide, chromium trioxide or seleniumdioxide. Suitable solvents to be used for this reaction may be ketonessuch as acetone and butan-2-one, or halogenated hydrocarbons such aschloroform, dichloromethane and dichloroethane or any mixtures thereof.The temperature may be between 0 and 80° C. and the reaction time may bebetween 3 and 50 h. The subsequent reduction is typically carried outusing sodium borohydride in methanol.

Abbreviations

-   alloc allyloxycarbonyl-   DCE dichloroethane-   DCM dichloromethane-   DMAP dimethylaminopyridine-   EDC 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride-   HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   HPLC high performance liquid chromatography-   LC liquid chromatography-   MsCl methanesulfonyl chloride-   MS mass spectometry-   ret. time retention time-   TFA trifluroacetic acid

A further embodiment of the invention relates to compounds

allyl (5-amino-1,3-benzothiazol-2-yl)methyl carbonate,

4-tert-Butyl-N-(2-formyl-1,3-benzothiazol-5-yl)-benzamide, and

4-Bromo-2-methyl-benzothiazol-5-ylamine, and

4-chloro-2-methyl-benzothiazole-5-ylamine.

Another embodiment relates to the used of these compounds asintermediates in the preparation of the compound of formula I.

Pharmaceutical Composition

According to one embodiment of the present invention there is provided apharmaceutical composition comprising as active ingredient atherapeutically effective amount of the compound of formula I, or salts,solvates or solvated salts thereof, in association with one or morepharmaceutically acceptable diluents, excipients and/or inert carriers.

The composition may be in a form suitable for oral administration, forexample as a tablet, pill, syrup, powder, granule or capsule, forparenteral injection (including intravenous, subcutaneous,intramuscular, intravascular or infusion) as a sterile solution,suspension or emulsion, for topical administration e.g. as an ointment,patch or cream or for rectal administration e.g. as a suppository.

In general the above compositions may be prepared in a conventionalmanner using one or more conventional excipients, pharmaceuticalacceptable diluents and/or inert carriers. Suitable daily doses of thecompounds of formula I in the treatment of a mammal, including man, areapproximately 0.01 to 250 mg/kg bodyweight at peroral administration andabout 0.001 to 250 mg/kg bodyweight at parenteral administration.

The typical daily dose of the active ingredient varies within a widerange and will depend on various factors such as the relevantindication, severity of the illness being treated, the route ofadministration, the age, weight and sex of the patient and theparticular compound being used, and may be determined by a physician.

Examples of Pharmaceutical Composition

The following illustrate representative pharmaceutical dosage formscontaining a compound of formula I, or salts, solvates or solvated saltsthereof, (hereafter compound X), for preventive or therapeutic use inmammals: (a): Tablet mg/tablet Compound X 100 Lactose 182.75Croscarmellose sodium 12.0 Maize starch paste (5% w/v paste) 2.25Magnesium stearate 3.0 (b): Capsule mg/capsule Compound X 10 Lactose488.5 Magnesium stearate 1.5 (c): Injection (50 mg/ml) Compound X 5.0%w/v 1M Sodium hydroxide solution 15.0% v/v 0.1M Hydrochloric acid (toadjust pH to 7.6) Polyethylene glycol 400 4.5% w/v Water for injectionup to 100%

The above compositions may be obtained by conventional procedures wellknown in the pharmaceutical art.

Medical Use

Surprisingly, it has been found that the compounds according to thepresent invention are useful in therapy. The compounds of formula I, orsalts, solvates or solvated salts thereof, as well as theircorresponding active metabolites, exhibit a high degree of potency andselectivity for individual vanilloid receptor 1 (VR1) groups.Accordingly, the compounds of the present invention are expected to beuseful in the treatment of conditions associated with excitatoryactivation of vanilloid receptor 1 (VR1).

The compounds may be used to produce an inhibitory effect of VR1 inmammals, including man.

VR1 are highly expressed the peripheral nervous system and in othertissues. Thus, it is expected that the compounds of the invention arewell suited for the treatment of VR1 mediated disorders.

The compounds of formula I are expected to be suitable for the treatmentof acute and chronic pain, acute and chronic neuropathic pain and acuteand chronic inflammatory pain.

Examples of such disorder may be selected from the group comprisingarthritis, fibromyalgia, low back pain, post-operative pain, visceralpains like chronic pelvic pain, cystitis, including interstitialcystitis, bowel syndrome (IBS), pancreatitis, ischeamic, sciatia,diabetic neuropathy, multiple sclerosis, HIV neuropathy, asthma, coughand inflammatory bowel disease (IBD).

Further relevant disorders may be selected from the group comprisinggastro-esophageal reflux disease (GERD), psoriasis, cancer, emesis,urinary incontinence and hyperactive bladder.

Other relevant disorders are related to respiratory diseases and may beselected from the group comprising asthma, chronic obstructive lungdisease and emphysema, lung fibrosis and interstitial lung disease.

The VR1 inhibitor(s) may be administrated by either an oral or inhaledroute. The respiratory disease may be an acute and chronic illness andmay be related to infection(s) and/or exposure to environmentalpollution and/or irritants.

The compounds of formula I may also be used as antitoxin to treat(over-) exposure to VR1 activators like capsaicin, tear gas, acids orheat. Regarding heat, there is a potential use for VR1 antagonists in(sun-) burn induced pain, or inflammatory pain resulting from bruninjuries.

The compounds may further be used for treatment of tolerance to VR1activators. One embodiment of the invention relates to the use of thecompounds of formula I as hereinbefore defined, in therapy.

Another embodiment of the invention relates to the use of the compoundsof formula I as hereinbefore defined, for treatment of VR1 mediateddisorders.

A further embodiment of the invention relates to the use of thecompounds of formula I as hereinbefore defined, for treatment of acuteand chronic pain disorders.

Yet another embodiment of the invention relates to the use of thecompounds of formula I as hereinbefore defined, for treatment of acuteand chronic neuropathic pain.

Yet a further embodiment of the invention relates to the use of thecompounds of formula I as hereinbefore defined, for treatment of acuteand chronic inflammatory pain.

One embodiment of the invention relates to the use of the compounds offormula I as hereinbefore defined, for treatment of arthritis,fibromyalgia, low back pain, post-operative pain, visceral pains likechronic pelvic pain, cystitis, IBS, pancreatitis or ischeamic.

Another embodiment of the invention relates to the use of the compoundsof formula I as hereinbefore defined, for treatment of sciatia, diabeticneuropathy, multiple sclerosis or HIV neuropathy.

A further embodiment of the invention relates to the use of thecompounds of formula I as hereinbefore defined, for treatment of asthma,cough, IBD, psoriasis, gastro-esophageal reflux disease (GERD),psoriasis, cancer, emesis, urinary incontinence or hyperactive bladder.

Yet another embodiment of the invention relates to the use of thecompounds of formula I as hereinbefore defined, for treatment ofinterstitial cystitis and pain related to interstitial cystitis.

Yet a further embodiment of the invention relates to the use of thecompound of formula I as hereinbefore defined, for the treatment ofrespiratory diseases selected from the group comprising asthma, chronicobstructive lung disease and emphysema, lung fibrosis and interstitiallung disease.

One embodiment of the invention relates to the use of the compound offormula I as hereinbefore defined, in the manufacture of a medicamentfor treatment of VR1 mediated disorders and for treatment of acute andchronic pain disorders, acute and chronic neuropathic pain and acute andchronic inflammatory pain and any other disorder mentioned above.

Another embodiment of the invention relates to a method of treatment ofVR1 mediated disorders and acute and chronic pain disorders, acute andchronic neuropathic pain and acute and chronic inflammatory pain, andrespiratory diseases, and any other disorder mentioned above, comprisingadministrering to a mammal, including man in need of such treatment, atherapeutically effective amount of the compounds of formula I, ashereinbefore defined.

A further embodiment of the invention relates to a pharmaceuticalcomposition comprising a compound of formula I as hereinbefore defined,for use in treatment of VR1 mediated disorders and for treatment ofacute and chronic pain disorders, acute and chronic neuropathic pain andacute and chronic inflammatory pain and any other disorder mentionedabove.

In the context of the present specification, the term “therapy” and“treatment” includes prevention and prophylaxis, unless there arespecific indications to the contrary. The terms “treat”,“therapeutic”and “therapeutically” should be construed accordingly.

In this specification, unless stated otherwise, the term “inhibitor” and“antagonist” mean a compound that by any means, partly or completely,blocks the transduction pathway leading to the production of a responseby the ligand.

The term “disorder”, unless stated otherwise, means any condition anddisease associated with vanilloid receptor activity.

Non-Medical Use

In addition to their use in therapeutic medicine, the compounds offormula I, or salts, solvates or solvated salts thereof, are also usefulas pharmacological tools in the development and standardisation of invitro and in vivo test systems for the evaluation of the effects ofinhibitors of VR1 related activity in laboratory animals such as cats,dogs, rabbits, monkeys, rats and mice, as part of the search for newtherapeutics agents.

EXAMPLES

The invention will now be illustrated by the following non-limitingexamples.

General Methods

All starting materials are commercially available or described in theliterature. The ¹H NMR spectra were recorded on Brucker at 400 MHz. Themass spectra were recorded utilising electrospray (LC-MS; LC:Waters2790, column XTerra MS C₈ 2.5 μm 2.1×30 mm, buffer gradient H₂O+0.1%TFA:CH₃CN+0.04% TFA, MS: micromass ZMD//ammonium acetate buffer)ionisation techniques.

Synthesis of Aromatic Amines as Starting Materials employed in amidebond-forming reactions in examples 1-17.

Allyl (5-amino-1,3-benzothiazol-2-yl)methyl carbonate A. tert-Butyl(2-methyl-1,3-benzothiazol-5-yl)carbamate

A mixture of Et₃N (100 mL), di-tert-butyl dicarbonate (58.3 g, 267 mmol)and 5-amino-2-methylbenzothiazole (22.0 g, 134 mmol) in MeOH (300 mL)was stirred at 65° C. for 2 hours and room temperature for 18 hours. Themixture was concentrated under reduced pressure, and the residue wasdiluted with DCM and washed with a 1M solution of HCl. The organic phasewas dried with Na₂SO₄, filtered and evaporated under reduced pressure toyield the carbamate derivative. R_(f)=0.45 (hexanes:EtOAc, 1:1); MS [M+]calc. 264.0, found 264.9.

B. tert-Butyl [2-(hydroxymethyl)-1,3-benzothiazol-5-yl]carbamate

SeO₂ (45.0 g, 402 mmol) was ground to a fine powder and added to asolution of the carbamate in dioxane (300 mL). The mixture was keptunder a N₂ atmosphere and heated to 70° C. for 18 hours with vigorousstirring. The mixture was quickly filtered and the solid was washed withhot dioxane. The filtrate was concentrated under reduced pressure toyield the aldehyde. R_(f)=0.56 (hexanes:EtOAc, 1:1). The crude aldehydewas dissolved in MeOH (300 mL) and NaBH₄ (15.21 g, 402 mmol) was addedportion-wise. The mixture was stirred for 2 hours and then diluted with1M NaOH. The mixture was evaporated to dryness, dissolved in DCM, washedwith a saturated solution of NaHCO₃, dried with Na₂SO₄, filtered andconcentrated under reduced pressure. R_(f)=0.09 (hexanes:EtOAc, 2:1); MS[M+] calc. 280.0 found 280.9.

C. Allyl {5-[(tert-butoxycarbonyl)amino]-1,3-benzothiazol-2-yl)methylcarbonate

The primary alcohol was dissolved in DCM (300 mL), andallylchloroformate (16.2 mg, 134 mmol) was added followed by DMAP (14.2g, 140 mmol). The mixture was stirred for 3 hours, and the solvent wasevaporated. MS [M+] calc. 364.0 found 364.9.

D. Allyl (5-amino-1,3-benzothiazol-2-yl)methyl carbonate

The alloc-protected derivative was dissolved in DCM (300 mL), and TFA(100 mL) was added. The mixture was stirred for 18 hours, and thenconcentrated under reduced pressure. The product was purified by flashchromatography on silica gel eluting with mixtures of heptane and EtOAc(4:1, 7:3 and 1:1) to yield an off-white powder (6.6 g, 25 mmol). ¹H NMR(400 MHz, CHLOROFORM-D) δ ppm 4.71 (d, J=5.86 Hz, 2 H) 5.30 (dd,J=10.35, 1.17 Hz, 1 H) 5.37 (q, J=3.0, 1.50 Hz, 1 H) 5.42 (q, J=3.0,1.50 Hz, 1 H) 5.51 (s, 2 H)5.95 (m, 1 H) 7.10 (s, 1 1 H) 7.63 (s, 1 H)7.70 (d, J=8.01 Hz, 1 H); ¹³C NMR (101 MHz, DMSO-D6) δ ppm 65.9, 68.5,110.7, 117.5, 118.7, 122.9, 126.9, 131.9, 140.5, 153.4, 153.9, 166.7; MS[M+] calc. 264.0 found 264.8.

Allyl (5-amino-4-chloro-1,3.benzothiazol-2-yl)methyl carbonate

Allyl (5-amino-1,3-benzothiazol-2-yl)methyl carbonate (500 mg, 1.89mmol) was dissolved in DCM (19.0 mL) and N-chlorosuccinimide (253 mg,1.89 mmol) was added. The mixture was stirred at ambient temperatureuntil the reaction appeared complete by LC-MS. The solution wasconcentrated under reduced pressure and purified by flash chromatographyusing mixtures of hexanes and EtOAc (4:1, 2:1) as an eluent to yield thetitle product (429 mg, 1.44 mmol, 76%). ¹H NMR (400 MHz, chloroform-D) δppm 2.77 (s, 2H) 4.71 (dt, J=5.86, 2.73, 1.37 Hz, 2 H) 5.27-5.46 (m, 2H) 5.57 (s, 2 H) 5.89-6.05 (m, 1 H) 6.92 (d, J=8.59 Hz, 1 H) 7.55 (d,J=8.59 Hz, 1 H).

4-Bromo-2-methyl-1,3-benzothiazol-5-ylamine and4,6-Dibromo-2-methyl-benzothiazol-5-ylanine

5-Amino-2-methylbenzothiazole (2.45 g, 14.9 mmol) and Br₂ (2.38 g, 14.9mmol) were mixed in CHCl₃ (60.0 mL) and stirred for 45 minutes. 28%NH₄OH (20.0 mL) was added, and the aqueous phase was extracted with DCM.The combined organic phases were dried with MgSO₄, filtered andevaporated. The products were separated from by flash chromatography onsilica gel eluting with mixtures of hexanes and EtOAc (4:1) to yield4-bromo-2-methyl-1,3-benzothiazol-5-ylamine: LC ret. time 1.13 minutes(Column: Phenomonex Polar, Gradient: 10-95% B, Flow rate: 1.75 mL/min,Column temperature: 40° C., Mobile phase: A-0.1% TFA in H₂O, B-0.1% TFAin MeCN), MS [M+] calcd. 242.0, found 242.0; and4,6-dibromo-2-methyl-benzothiazol-5-ylamine: LC ret. time 1.64 minutesMS [M+] calcd. 322.0, found 322.0

5-Amino-1,3-benzothiazole-2-carbaldehyde

Manganese dioxide (10 mmol) was added to a solution of5-amino-2-methylbenzothiazole (2 mmol) in acetone (20 mL ). The mixturewas refluxed for 24 h. After cooling to ambient temperature, the mixturewas filtered and concentrated in vacuo to afford crude5-amino-2-formylbenzothiazole as a yellow oil which was used for thenext step without further purification. MS [M+] calc. 178.2, found 179

Example 14-tert-Butoxy-N-[2-(hydroxymethyl)-1,3-benzothiazol-5-yl]benzamide

A. Synthesis of the O-Alloc Protected Derivative

Allyl (5-amino-1,3-benzothiazol-2-yl)methyl carbonate (see above) (97.0mg, 0.370 mmol) and 4-tert-butoxybenzoic acid (71.0 mg, 0.370 mmol) weremixed in a mixture of DCM (5.00 mL) and DMF (5.00 mL) with EDC (220 mg,1.15 mmol) and DMAP (236 mg, 1.15 mmol). ). The mixture was stirred for18 hours, and the solvents were evaporated. The residue was dissolved inDCM and washed with a saturated solution of NaHCO₃. The mixture wasdried with Na₂SO₄, filtered and concentrated under reduced pressure. Thecrude product was purified by Gilson reverse phase HPLC (Luna 15 u, C18(2) 250 mm×21.2 mm), eluting with mixtures of H₂O and MeCN with 0.1% TFAthe O-alloc protected derivative of the title compound: MS [M+] calc.440.0 found 440.9.

B. Deprotection

The product obtained in Part A was treated with a solution of Pd(OAc)₂(10.0 mg), PPh₃ (20.0 mg) and Et₃SiH (176 mg, 1.52 mmol, 0.240 mL) in amixture of THF (4.00 mL) and DMF (4.00 mL). The mixture was stirred atroom temperature until the reaction appeared complete by TLC analysis,and the solvents were evaporated. The crude product was purified byGilson HPLC (Luna 15 u, C18 (2), 250 mm×21.2 mm) eluting with mixture ofMeCN and H₂O containing 1% TFA to yield the title product. ¹H NMR (400MHz, methanol-D4) δ ppm 1.42 (s, 9 H) 4.95 (s, 2 H) 7.12 (m, 2 H) 7.71(dd, J=8.79, 1.17 Hz, 1 H) 7.91 (m, 2 H) 7.96 (d, J=8.79 Hz, 1 H) 8.40(s, 1 H); MS [M+H] calc. 357.1 found 10 357.0; Anal. found C 64.61% H5.58% N 6.65%.

Example 2 4-Bromo-N-[2-(hydroxymethyl)-1,3-benzothiazol-5-yl]benzamide

4-Bromobenzoylchloride (0.4 mmol) was dissolved in DCM and DMAP (0.4mmol) was added. The mixture was stirred for 10 minutes and then allyl(5-amino-1,3-benzothiazol-2-yl)methyl carbonate (100 mg, 0.38 mmol) wasadded. The mixture was stirred until the reaction appeared complete byTLC analysis and NaOH (1M) was added. The aqueous phase was extractedwith DCM. The organic phases were collected, dried with Na₂SO₄, filteredand concentrated under reduced pressure. Purification by HPLC affordedthe O-alloc protected derivative of the title compound: MS [M+1] calc.448.0 found 448.4. Deprotection according to the procedure described inExample 1, part B afforded the title compound; δ ppm 4.79 (s, 2H) 7.55(d, J=8.3 Hz, 3 H) 7.74 (d, J=8.4 Hz, 2 H) 7.8 (d, J=8.7 Hz, 1 H) 8.25(s, 1 H); MS [M+H] calc. 363.2 found 363.0.

Compounds in the following examples were synthesized according to theamide bond-forming procedures described in the examples 1 or 2 startingfrom an appropriate aromatic amine, either commercially available orsynthesized according to the procedures described above, and anappropriately substituted commercially available aromatic acid or anaromatic acyl chroride. Where appropriate the amide bond-formingprocedures were followed by the deprotection as described in Example 1MW Example MW found number Name calcd [M + 1] ¹H NMR  3N-[2-(Hydroxymethyl)- 411.1 411.0 (600MHz, methanol-D₄) δppm1,3-benzothiazol-5-yl]-4- 4.79(s, 2H) 7.55(d, iodobenzamide J=8.3Hz, 3H)7.74(d, J=8.4Hz, 2H) 7.80(d, J=8.7Hz, 1H) 8.25(s, 1H)  4N-[2-(Hydroxymethyl)- 370.1 370.0 (400MHz, DMSO-D₆) δppm1,3-benzothiazol-5-yl]-4- 3.24(m, 4H), 3.73(m, 4H)morpholin-4-ylbenzamide 4.83(d, J=6.05Hz, 2H) 6.22(t, J=5.96Hz, 1H)7.02(d, J=9.18Hz, 2H) 7.76(dd, J=8.69, 2.05Hz, 1H) 7.90(d, J=9.18Hz, 2H)7.98(d, J=8.79Hz, 1H) 8.42(d, J=1.95Hz, 1H) 10.13(s, 1H)  5N-{2-[(Allyloxy)methyl]- 410.2 410.0 (400MHz, methanol-D₄) δppm (no1,3-benzothiazol-5-yl}-4- 3.09(m, 4H), 3.73(m, 4H) deprotectionmorpholin-4-ylbenzamide 4.58(d, J=6.05Hz, 2H) step 4.90(s, 2H) 5.16(m,2H) required) 5.99(m, 1H) 6.70(m, 2H) 7.22(m, 3H) 7.62(d, J=1.95Hz, 1H)7.87(d, J=8.59Hz, 1H)  6 N-[2-(Hydroxymethyl)- 393.1 392.9 (400MHz,methanol-D₄) δppm 1,3-benzothiazol-5-yl]-1- 3.09(m, 4H), 3.73(m, 4H)phenyl-5-propyl-1H- 4.58(d, J=6.05Hz, 2H) pyrazole-4-carboxamide 4.90(s,2H) 5.16(m, 2H) 5.99(m, 1H) 6.70(m, 2H) 7.22(m, 3H) 7.62(d, J=1.95Hz,1H) 7.87(d, J=8.59Hz, 1H)  7 1-tert-Butyl-N-[2- 345.1 345.0 (400MHz,methanol-D₄) δppm (hydroxymethyl)-1,3- 1.71(s, 9H) 2.52(s, 3H)benzothiazol-5-yl]-3- 4.95(s, 2H) 6.61(s, 1H) methyl-1H-pyrazole-5-7.69(dd, J=8.69, 1.85Hz, 1H) carboxamide 7.93(d, J=8.79Hz, 1H) 8.43(d,J=1.95Hz, 1H)  8 4-(Ethoxymethyl)-N-[2- 343.1 343.0 (400MHz,methanol-D₄) δppm (hydroxymethyl)-1,3- 1.24(t, J=7.03Hz, 3H)benzothiazol-5- 3.58(q, J=7.03Hz, 2H) yl]benzamide 4.58(s, 2H) 4.95(s,2H) 7.48(d, J=8.59Hz, 2H) 7.71(dd, J=8.69, 2.05Hz, 1H) 7.92(s, 1H)7.94(d, J=7.81Hz, 2H) 8.41(d, J=1.95Hz, 1H)  9 N-[2-(Hydroxymethyl)-335.1 335.0 (400MHz, chloroform-D) δppm 1,3-benzothiazol-5-yl]-1-2.78(s, 3H) 6.79(d, phenyl-1H-pyrazole-5- J=1.76Hz, 1H) 7.35(m, 5H)carboxamide 7.60(m, 3H) 7.89(s, 1H) 10 4-Bromo-N-[2- 377.0 377.0(400MHz, methanol-D₄) δppm (hydroxymethyl)-1,3- 2.45(s, 3H) 4.95(s, 2H)benzothiazol-5-yl]-2- 7.40(d, J=8.20Hz, 1H) methylbenzamide 7.45(m, 1H)7.49(s, 1H) 7.66(dd, J=8.69, 2.05Hz, 1H) 7.93(d, J=8.59Hz, 1H) 8.40(d,J=1.95Hz, 1H) 11 4-tert-Butoxy-N-(2- 325.1 325.2 (400MHz, chloroform-D)

ppm methyl-1,3-benzoxazol-5- 1.41(s, 9H) 2.63(s, 3H) yl) benzamide7.07(m, 2H) 7.43(d, J=8.79Hz, 1H) 7.58(dt, J=8.79, 2.15Hz, 1H) 7.82(m,2H) 7.89(d, J=1.95Hz, 1H) 7.98(s, 1H) 12 N-(4-Bromo-2-methyl-1,3- 403.0403.0 (400MHz, chloroform-D) δppm benzothiazol-5-yl)-4-tert- 1.38(s, 9H)2.90(s, 3H) butylbenzamide 7.56(d, J=8.59Hz, 2H) 7.79(d, J=8.79Hz, 1H)7.93(d, J=8.59Hz, 2H) 8.63(d, J=8.98Hz, 1H) 13 4-tert-Butyl-N-(4,7-481.0 480.7 (400MHz, methanol-D₄) δppm dibromo-2-methyl-1,3- 1.37(s, 9H)2.85(s, 3H) benzothiazol-5- 7.58(d, J=8.40Hz, 2H) yl)benzamide 7.97(d,J=8.40Hz, 2H) 8.31(s, 1H) 14 N-[2-(hydroxymethyl)-1,3- 419.1 419.0(400MHz, methanol-D4) δppm benzothiazol-5-yl]-1- 4.95(m, 2H), 7.59(m,6H), phenyl-5- 7.96(m, 1H), 8.14(m, 1H), (trifluoromethyl)-1H- 8.37(m,1H). pyrazole-4-carboxamide 15 4-Iodo-N-(2-methyl-5- 395.0 394.8(400MHz, chloroform-D) δppm benzothiazolyl)benzamide 2.84(s, 3H) 7.64(d,J=8.59Hz, 2H) 7.73(dd, J=8.59, 1.95Hz, 1H) 7.80(m, 1H) 7.86(d, J=8.59Hz,2H) 7.94(m, 1H) 8.14(d, J=1.95Hz, 1H) 16 4-(tert-Butoxymethyl)-N- 371.1371.0 (400MHz, methanol-D₄) δppm [2-(hydroxymethyl)-1,3- 1.30(s, 9H)4.54(s, 2H) benzothiazol-5- 4.94(s, 2H) 7.48(d, J=8.59Hz, yl]benzamide2H) 7.71(dd, J=8.69, 2.05Hz, 1H) 7.92(m, 3H) 8.39(d, J=1.56Hz, 1H) 17N-(1,2-Dimethyl-1H- 392.0 392.0 (400MHz, DMSO-D₆) δppmbenzimidazol-5-yl)-4- 2.75(s, 3H) 3.87(s, 3H) iodobenzamide 7.75(d,J=8.59Hz, 2H) 7.80(t, J=2.05Hz, 1H) 7.84(d, J=8.98Hz, 1H) 7.92(d,J=8.40Hz, 2H) 8.32(t, J=2.15Hz, 1H) 10.58(s, 1H) 18N-[2-(Hydroxymethyl)- 450.1 451.0 (400MHz, methanol-D4) δppm1,3-benzothiazol-5-yl]-4- 4.95(s, 2H) 7.72(d,[2,2,2-trifluoro-1-hydroxy- J=8.59Hz, 1H) 7.90(d, 1- J=8.40Hz, 2H)7.96(d, (trifluoromethyl)ethyl]benzamide J=8.59Hz, 1H) 8.04(d, J=8.59Hz,2H) 8.40-8.46(m, 1H) 10.43(s, 1H) 19 N-[2-(Hydroxymethyl)- 343.1 343.0(400MHz, methanol-D4) δppm 1,3-benzothiazol-5-yl]-4- 1.31(d, J=6.05Hz,6H) isopropoxybenzamide 4.65(dt, J=11.96, 6.03Hz, 1H) 4.93(s, 2H)6.95(d, J=8.98Hz, 2H) 7.66(dd, J=8.59, 1.76Hz, 1H) 7.85-7.91(m, 2H)8.36(s, 1H) 20 4-Bromo-2-chloro-N-[2- 397.0 396.7 (400MHz, DMSO-D6) δppm(hydroxymethyl)-1,3- 4.82(s, 2H) 6.23(t, J=12.11, benzothiazol-5-6.05Hz, 1H) 7.58(d, J=8.20Hz, yl]benzamide 1H) 7.63(dt, J=8.79, 3.32,2.15Hz, 1H) 7.68(dd, J=8.20, 1.95Hz, 1H) 7.88(d, J=1.95Hz, 1H) 8.01(d,J=8.59Hz, 1H) 8.35(t, J=1.66Hz, 1H) 10.70(s, 1H) 214-Bromo-2-fluoro-N-[2- 381.0 381.0 (400MHz, chloroform-D) δppm(hydroxymethyl)-1,3- 5.09(s, 2H) 7.43(d, benzothiazol-5- J=11.52Hz, 1H)7.50(dd, yl]benzamide J=8.40, 1.56Hz, 1H) 7.71(s, 1H) 7.88(d, J=8.59Hz,1H) 8.11(t, J=8.49Hz, 1H) 8.33(s, 1H) 8.52(s, 1H) 22N-[2-(Hydroxymethyl)- 384.1 384.0 (400MHz, methanol-D4) δppm1,3-benzothiazol-5-yl]-4- 3.18-3.46(m, 4H) (morpholin-4- 3.75(s, 2H)3.94-4.17(m, 2H) ylmethyl)benzamide 4.47(s, 2H) 4.96(s, 2H) 7.65-7.75(m,3H) 7.98(d, J=8.79Hz, 1H) 8.10(d, J=8.20Hz, 2H) 8.42(d, J=1.56Hz, 1H) 233-Fluoro-N-[2- 371.0 371.0 (400MHz, methanoL-D4) δppm(hydroxymethyl)-1,3- 4.95(s, 2H) 7.73(dd, benzothiazol-5-yl]-4- J=8.69,1.86Hz, 1H) (trifluoromethyl)benzamide 7.83-8.01(m, 4H) 8.43(d,J=1.76Hz, 1H) 24 4-tert-butoxy-N-[4-chloro- 391.1 391.0 (400MHz,methanol-D4) δppm 2-(hydroxymethyl)-1,3- 1.42(s, 9H) 4.98(s, 2H)benzothiazol-5- 7.13(d, J=8.59Hz, 2H) yl]benzamide 7.75(d, J=8.59Hz, 1H)7.88-7.98(m, 3H) 25 4-(tert-Butoxymethyl)-N- 405.1 405.0 (400MHz,methanol-D4) δppm [4-chloro-2- 1.26-1.36(m, 9H) (hydroxymethyl)-1,3-4.57(s, 2H) 4.98(s, 2H) 5.48(s, 1H) benzothiazol-5- 7.51(d, J=8.20Hz,2H) yl]benzamide 7.75(d, J=8.59Hz, 1H) 7.97(dd, J=8.40, 2.73Hz, 3H) 263-Fluoro-N-(2-methyl-1,3- 354.3 355.0 benzothiazol-5-yl)-4-trifluoromethyl-benzamide 27 2-tert-Butyl-5-methyl-2H- 328.4 329pyrazole-3-carboxylic acid (2-methyl-1,3- benzothiazol-5-yl)-amide 282-Fluoro-N-(2-methyl-1,3- 354.3 355.0 benzothiazol-5-yl)-4-trifluoromethyl-benzamide 29 2-Fluoro-N-(2-methyl-1,3- 354.3 354.0benzothiazol-5-yl)-3- trifluoromethyl-benzamide 304-Fluoro-N-(2-methyl-1,3- 354.3 354.0 benzothiazol-5-yl)-3-trifluoromethyl-benzamide 31 3,4-Dimethyl-N-(2- 296.4 297.1methyl-benzothiazol-5-yl)- benzamide 32 2,2-Difluoro- 348.3 349benzo[1,3]dioxole-5- carboxylic acid (2-methyl- 1,3-benzothiazol-5-yl)-amide 33 N-(2-Methyl-1,3- 337.3 338 benzothiazol-5-yl)-6-trifluoromethyl- nicotinamide 34 N-(2-Methyl-1,3- 310.4 311.1benzothiazol-5-yl)-4- propyl-benzamide 35 3-Iodo-N-(2-methyl-1,3- 394.23394.9 benzothiazol-5-yl)- benzamide 36 2,5-Dimethyl-furan-3- 286.35 287carboxylic acid (2-methyl- 1,3-benzothiazol-5-yl)- amide 375-tert-Butyl-2-methyl- 328.43 329.1 furan-3-carboxylic acid (2-methyl-1,3-benzothiazol- 5-yl)-amide 38 4-Bromo-3-methyl-N-(2- 361.26360.99 methyl-1,3-benzothiazol- 5-yl)-benzamide 393,4-Difluoro-N-(2-methyl- 304.32 305 1,3-benzothiazol-5-yl)- benzamide40 3-Chloro-2-fluoro-N-(2- 320.77 321 methyl-1,3-benzothiazol-5-yl)-benzamide 41 Pyridine-2-carboxylic acid 269.33 270 (2-methyl-1,3-benzothiazol-5-yl)-amide 42 2-Benzyl-5-tert-butyl-2H- 404.54 405.1pyrazole-3-carboxylic acid (2-methyl-1,3- benzothiazol-5-yl)-amide 433-Fluoro-4- 391.25 392 trifluoromethyl-N-(2- trifluoromethyl-1H-benzimidazol-5-yl)- benzamide 44 2-Fluoro-5- 391.25 392trifluoromethyl-N-(2- trifluoromethyl-1H- benzimidazol-5-yl)- benzamide45 4-Chloro-N-(2-methyl- 302.8 302.9 (400MHz, DMSO-D6) δppmbenzothiazol-5-yl)- 2.8(s, 3H) 7.6(d, J=8.6Hz, 2H) benzamide 7.8(d,J=9.1Hz, 1H) 8.0(m, 3H) 8.4(s, 1H) 10.5(s, 1H) 46 1-Phenyl-5- 402.4402.9 (400MHz, DMSO-D6) δppm trifluoromethyl-1H- 2.8(s, 3H) 7.5(m, 2H)pyrazole-3-carboxylic acid 7.6(m, 3H) 7.7(d, J=9.1Hz, 1H) (2-methyl-1,3-8.0(d, J=8.6Hz, 1H) benzothiazol-5-yl)-amide 8.3(m, 2H) 10.7(s, 1H) 471-Phenyl-5-propyl-1H- 376.5 376.9 (400MHz, chloroform-D) δppmpyrazole-4-carboxylic acid 0.8(t, J=7.3Hz, 3H) (2-methyl-1,3- 1.5(m, 2H)2.8(s, 3H) 2.9(m, 2H) benzothiazol-5-yl)-amide 7.4(m, 2H) 7.4(m, 3H)7.7(s, 1H) 7.7(m, 2H) 7.9(s, 1H) 8.0(m, 1H) 48 2,3-Difluoro-N-(2-methyl-372.3 372.7 (400MHz, chloroform-D) δppm 1,3-benzothiazol-5-yl)-4- 2.8(s,3H) 7.5(t, J=7.3Hz, trifluoromethyl-benzamide 1H) 7.7(dd, J=8.6, 2.0Hz,1H) 7.8(d, J=8.6Hz, 1H) 8.0(t, J=7.6Hz, 1H) 8.2(d, J=2.0Hz, 1H) 8.4(d,broad, 1H) 49 3-Fluoro-4-methyl-N-(2- 300.4 300.8methyl-1,3-benzothiazol- 5-yl)-benzamide 50 4-tert-Butyl-N-(2-methyl-324.5 325.2 (400MHz, chloroform-D) δppm 1,3-benzothiazol-5-yl)- 1.4(s,9H) 2.8(s, 3H) benzamide 7.5(d, J=8.6Hz, 2H) 7.8(m, 2H) 7.8(d, J=8.6Hz,2H) 7.9(s, 1H) 8.1(m, 1H) 51 4-Ethyl-N-(2-methyl-1,3- 296.4 297.2benzothiazol-5-yl)- benzamide 52 4-tert-Butyl-N-(2-methyl- 308.4 3091,3-benzooxazol-5-yl)- benzamide 53 Biphenyl-4-carboxylic 344.4 345 acid(2-methyl-1,3- benzothiazol-5-yl)-amide 54 3-Bromo-thiophene-2- 353.3354 (400MHz, chloroform-D) δppm carboxylic acid (2-methyl- 2.84(s, 3H)7.11(d, 1,3-benzothiazol-5-yl)- J=5.27Hz, 1H) 7.54(d, amide J=5.27Hz,1H) 7.73(dd, J=8.79, 2.15Hz, 1H) 7.80(d, J=8.59Hz, 1H) 8.20(d, J=1.95Hz,1H) 8.98(s, 1H) 55 4-Bromo-2-methyl-N-(2- 361.3 362 (400MHz,chloroform-D) δppm methyl-1,3-benzothiazol- 2.50(s, 3H) 2.84(s, 3H)5-yl)-benzamide 7.42(d, J=19.14Hz, 2H) 7.64(s, 1H) 7.77(m, 3H) 8.10(s,1H) 56 4-tert-Butoxy-N-(2- 340.4 341 (400MHz, chloroform-D) δppmmethyl-1,3-benzothiazol- 1.41(m, 9H), 2.84(s, 3H), 5-yl)-benzamide7.09(d, J=8.79Hz, 2H), 7.78(m, 2H), 7.83(d, J=8.98Hz, 2H), 7.93(s, 1H),8.12(m, 1H) 57 2-Chloro-3,4-dimethoxy- 362.8 363 (400MHz, chloroform-D)δppm N-(2-methyl-1,3- 2.84(s, 3H), 3.90(s, 3H), benzothiazol-5-yl)-3.94(s, 3H), 6.94(d, benzamide J=8.79Hz, 1H), 7.62(d, J=8.79Hz, 1H),7.78(m, 2H), 8.18(s, 1H). 58 4-Iodo-N-(2-methyl-1,3- 394.2 395 (400MHz,chloroform-D) δppm benzothiazol-5-yl)- 2.84(s, 3H) 7.64(d, benzamideJ=8.59Hz, 2H) 7.73(dd, J=8.59, 1.95Hz, 1H) 7.80(m, 1H) 7.86(d, J=8.59Hz,2H) 7.94(m, 1H) 8.14(d, J=1.95Hz, 1H) 59 4-Amino-N-(2-methyl-1,3- 328.4329 (400MHz, DMSO-D6) δppm benzothiazol-5-yl)-3-nitro- 2.79(s, 3H),7.10(d, J=8.98Hz, benzamide 1H), 7.75(m, 1H), 7.87(s, 2H), 7.96(d,J=8.59Hz, 1H), 8.01(dd, J=8.89, 2.25Hz, 1H), 8.39(m, 1H), 8.75(d,J=2.15Hz, 1H), 10.37(s, 1H) 60 N-(2-Methyl-1,3- 294.4 295 (400MHz,chloroform-D) δppm benzothiazol-5-yl)-4- 2.84(s, 3H) 5.40(d,vinyl-benzamide J=10.94Hz, 1H) 5.87(d, J=17.57Hz, 1H) 6.78(dd, J=17.57,10.94Hz, 1H) 7.52(d, J=8.20Hz, 2H) 7.78(m, 2H) 7.87(d, J=8.40Hz, 2H)7.99(s, 1H) 8.15(s, 1H) 61 4-Ethoxy-N-(2-methyl- 312.4 313 (400MHz,chloroform-D) δppm 1,3-benzothiazol-5-yl)- 1.45(t, J=7.03Hz, 3H)benzamide 2.83(s, 3H) 4.10(q, J=14.06, 7.03Hz, 2H) 6.96(d, J=8.98Hz, 2H)7.77(m, 2H) 7.88(d, J=6.83Hz, 2H) 7.98(s, 1H) 8.11(m, 1H) 624-Ethylsulfanyl-N-(2- 328.5 329 (400MHz, chloroform-D) δppmmethyl-1,3-benzothiazol- 1.37(t, J=7.42Hz, 3H) 5-yl)-benzamide 2.83(s,3H) 3.02(q, J=14.65, 7.22Hz, 2H) 7.33(d, J=8.79Hz, 2H) 7.76(s, 2H)7.81(d, J=8.59Hz, 2H) 8.13(s, 2H) 63 4-Dimethylamino- 361.5 362 (400MHz,chloroform-D) δppm naphthalene-1-carboxylic 2.85(s, 3H), 2.96(m, 6H),acid (2-methyl-1,3- 7.03(d, J=7.81Hz, 1H), benzothiazol-5-yl)-amide7.54(m, 2H), 7.72(d, J=7.81Hz, 1H), 7.83(m, 3H), 8.13(m, 1H), 8.26(m,1H), 8.43(m, 1H). 64 2-Fluoro-6-iodo-N-(2- 412.2 413methyl-1,3-benzothiazol- 5-yl)-benzamide 65 4-Ethoxymethyl-N-(2- 326.4327 (400MHz, chloroform-D) δppm methyl-1,3-benzothiazol- 1.27(t,J=14.06, 7.03Hz, 5-yl)-benzamide 3H) 2.84(s, 3H) 3.58(q, J=14.06,7.03Hz, 2H) 4.58(s, 2H) 7.47(d, J=8.59Hz, 2H) 7.78(m, 2H) 7.88(d,J=8.40Hz, 2H) 8.05(s, 1H) 8.14(s, 1H) 66 N-(2-Methyl-1,3- 352.3 353(400MHz, chloroform-D) δppm benzothiazol-5-yl)-4- 2.84(s, 3H) 7.33(d,trifluoromethoxy- J=8.79Hz, 2H) 7.77(m, 2H) benzamide 7.95(d, J=8.98Hz,2H) 8.00(s, 1H) 8.14(d, J=1.95Hz, 1H) 67 4-Chloro-3-fluoro-N-(2- 320.8321 (400MHz, DMSO-D6) δppm methyl-1,3-benzothiazol- 2.74(s, 3H), 7.70(m,1H), 5-yl)-benzamide 7.75(m, 1H), 7.82(dd, J=8.40, 1.95Hz, 1H), 7.96(m,2H), 8.396(m, 1H), 10.49(s, 1H) 68 4-tert-Butyl-N-(2-formyl- 338.4 339(400MHz, DMSO-D6)

1,3-benzothiazol-5-yl)- 1.35(s, 9H), 7.27(d, J=8.6Hz, 2H), benzamide7.60-7.73(m, 2H), 7.73(d, J=8.6Hz, 1H), 7.86(s, 1H), 8.13(s, 1H),8.84(s, 1H) 69 4-tert-Butyl-N-(2- 340.5 341 (400MHz, DMSO-D6) δhydroxymethyl-1,3- 1.30(s, 9H), 3.12(s, 1H), 4.42(s, benzothiazol-5-yl)-2H) 7.22(d, J=8.6Hz, 2H), benzamide 7.62-7.76(m, 2H), 7.83(d, J=8.6Hz,1H), 7.96(s, 1H), 8.25(s, 1H)

Example 704-tert-Butyl-N-(2-{[(2-methoxypyridin-3-yl)amino]methyl}-1,3-benzothiazol-5-yl)benzamide

A mixture of SeO₂ (4.44 g, 40.0 mmol) and4-tert-butyl-N-(2-methyl-benzothiazol-5-yl)-benzamide (16.0 mmol) indioxane (20.0 mL) was kept under a N₂ atmosphere and heated to 100° C.for 18 hours with vigorous stirring. After cooling to room temperature,the dioxane was removed by evaporation under reduced pressure. Theresulting residue was dissolved in EtOAc, washed with brine, dried withNa₂SO₄, filtered and concentrated under reduced pressure to yield thealdehyde, MS (ESI⁺) m/z 325.0 [M+H]⁺. The aldehyde (100 mg, 0.300 mmol)was mixed with 2-methoxypyridin-3-amine (36.0 mg, 0.300 mmol) and MgSO₄(100 mg) in THF (3.00 mL). After 18 hours, B₁₀H₄ (14.0 mg, 0.320 mmol)dissolved in MeOH (3.00 mL) was added. The mixture was stirred until thereaction appeared complete by TLC analysis. 1M NaOH was added and thesolvents were evaporated. The residue was purified by flashchromatography eluting with mixtures of hexanes and EtOAc (4:1, 1:1). ¹HNMR (400 MHz, chloroform-D) δ ppm 1.29 (s, 9 H) 3.98 (s, 3 H) 4.68 (d,J=5.86 Hz, 2 H) 6.67 (m, 2 H) 7.40 (dt, J=8.69, 2.10 Hz, 2 H) 7.51 (dd,J=4.69, 1.95 Hz, 1 H) 7.66 (d, J=1.17 Hz, 2 H) 7.80 (ddd, J=8.59, 2.25,2.05 Hz, 2 H) 8.25 (d, J=1.17 Hz, 1 H) 8.45 (s, 1 H); MS [M+H] calc.447.2 found 447.0.

Example 714-tert-Butyl-N-[2-(1-hydroxyethyl)-1,3-benzothiazol-5-yl]benzamide

Methylmagnesium bromide (276 uL, 3.0 M in Et₂O) was added dropwise viasyringe to a stirred solution of the aldehyde (obtained as anintermediate in Example 70) (100 mg, 0.30 mmol) in THF (10.0 mL) at −78°C. under nitrogen. After addition was complete the mixture was stirredfor additional 1 hour and quenched with saturated aqueous ammoniumchloride (2.0 mL). The mixture was diluted with EtOAc (25.0 mL) andwater (20.0 mL) and the organic phase was seaprated. The aqueous phasewas extracted with EtOAc (2×10.0 mL) and the organic phases combined andwashed with brine solution (30.0 mL). The organic was dried with Na₂SO₄,filtered and concentrated by rotary evaporator to a residue which waspurified by column chromatography on silica gel using EtOAc/hexanes asan eluent to yield the title product. ¹H NMR (400 MHz, methanol-D4) δppm 1.34 (s, 9 H), 1.62 (d, J=6.44 Hz, 3 H), 5.12 (m, 1 H), 7.54 (d,J=8.59 Hz, 2 H), 7.69 (dd, J=8.69, 2.05 Hz, 1 H), 7.89 (m, 3 H), 8.39(d, J=1.95 Hz, 1 H). MS [M+H] calc. 355.1 found 355.2.

Example 724-tert-Butyl-N-{2-[(1H-pyrazol-3-ylamino)methyl]-1,3-benzothiazol-5-yl}benzamide

The title compounds wa synthesized according to the procedure describedin Example 70 using 1H-pyrazol-3-amine at the reductive amination step.¹H NMR (400 MHz, methanol-D4) δ 1.31 (m, 9 H) 4.71 (s, 2 H) 5.62 (d,J=2.34 Hz, 1 H) 7.35 (d, J=2.34 Hz, 1 H) 7.53 (d, J=8.79 Hz, 2 H) 7.67(dd, J=8.69, 2.05 Hz, 1 H) 7.83 (d, J=8.59 Hz,1 H) 7.88 (d, J=8.79 Hz, 2H) 8.37 (d, J=1.76 Hz, 1 H); MS [M+H] calc. 406.2 found 406.0.

Example 734-(1,1-Dimethylethyl)-N-[2-[[(4-nitrophenyl)amino]methyl]-5-benzothiazolyl]-benzamide

The title compound was synthesized according to the procedure describedin Example 70 using p-nitroaniline at the reductive amination step. ¹HNMR (400 MHz, DMSO-D6) δ ppm 1.32 (s, 9 H), 4.91 (m, 2 H), 6.78 (d,J=9.18 Hz, 2 H), 7.56 (d, J=8.40 Hz, 2 H), 7.76 (dd, J=8.79, 1.95 Hz, 1H), 7.91 (d, J=8.40 Hz, 2 H), 7.97 (d, J=8.79 Hz, 1 H), 8.02 (d, J=9.18Hz, 2 H), 8.17 (t, J=6.25 Hz, 1 H), 8.50 (d, J=1.76 Hz, 1 H), 10.38 (s,1 H). MS [M+H] calc. 461.2 found 461.0.

Example 74N-[2-(Aminomethyl)-1,3-benzothiazol-5-yl]-4-tert-butylbenzamide

4-tert-Butyl-N-(2-hydroxymethyl-1,3-benzothiazol-5-yl)-benzamide (44.0mg, 0.380 mmol) was mixed with MsCl (40.0 mg, 0.390 mmol, 0.0540 mL) andEt₃N (51.0 mg, 0.500 mmol) in DCM (5.00 mL) and the solution was stirredfor 10 minutes. NH₃ (2.0M in EtOH) was added, and the mixture wasstirred for additional 18 hours. The solvent was evaporated, and thecrude product was purified by HPLC (Luna 15 u, C18 (2), 250 mm×21.2 mm)eluting with mixtures of MeCN and H₂O containing 1% TFA. ¹H NMR (400MHz, methanol-D4) δ ppm 1.21 (s, 9 H) 4.48 (s, 2 H) 7.41 (d, J=8.20 Hz,2 H) 7.57 (d, J=8.20 Hz, 1 H) 7.76 (d, J=8.20 Hz, 2 H) 7.83 (d, J=8.59Hz, 1 H) 8.47 (s, 1 H); MS [M+H] calc. 340.1 found 340.3.

Example 754-tert-Butyl-N-(2-{[(methylsulfonyl)amino]methyl}-1,3-benzothiazol-5-yl)benzamide

N-[2-(Aminomethyl)-1,3-benzothiazol-5-yl]-4-tert-butylbenzamide (example74) (130 mg, 0.384 mmol) was stirred with MsCl (44.0 mg, 0.387 mmol) andEt₃N (58.0 mg, 0.600 mmol, 0.0800 mL) in DCM (5.00 mL) for 1 hour. Thesolvent was evaporated, and the residue was purified by HPLC (Luna 15 u,C18 (2), 250 mm×21.2 mm) eluting with mixtures of MeCN and H₂Ocontaining 1% TFA to yield the title product. ¹H NMR (400 MHz,chloroform-D) δ ppm 1.35 (s, 9 H) 3.05 (s, 3 H) 4.79 (s, 2 H) 5.73 (s, 1H) 7.52 (d, J=8.59 Hz, 2 H) 7.80 (s, 2 H) 7.85 (d, J=8.40 Hz, 2 H) 8.12(s, 1 H) 8.23 (s, 1 H); MS [M+] calc. 417.5 found 417.9; Anal. found C54.39% H 5.43% N 8.71%.

Example 76N-{2-[(Acetylamino)methyl]-1,3-benzothiazol-5-yl}-4-tert-butylbenzamide

N-[2-(Aminomethyl)-1,3-benzothiazol-5-yl]-4-tert-butylbenzamide (example74) (60.0 mg, 0.18 mmol) was stirred with acetyl chloride (16.0 mg, 0.2mmol, 0.015 mL) and Et₃N (25.0 mg, 0.25 mmol) in DCM (5.00 mL) for 1hour. The solvent was evaporated, and the residue was purified by HPLCeluting with mixtures of MeCN and H₂O containing 1% TFA to yield thetitle product. ¹H NMR (400 MHz, chloroform-D) δ ppm 1.35 (s, 9 H) 2.12(s, 3 H) 4.84 (s, 2 H) 7.49 (d, J=8.40 Hz, 2 H) 7.68 (s, 1 H) 7.75 (d,J=8.79 Hz, 1 H) 7.84 (d, J=8.20 Hz, 2 H) 8.20 (s, 1 H) 8.64 (s, 1 H)11.35 (s, 1 H); MS [M+H] calc. 382.1 found 382.0; Anal. found C 55.85% H4.94% N 8.60%.

Example 775-[(4-tert-Butylbenzoyl)amino]-1,3-benzothiazole-2-carboxamide

The aldehyde (example 70) (100 mg, 0.3 mmol) was dissolved in THF (10.0mL) and a mixture of sodium chlorite (54.0 mg, 0.6 mmol) and sulfamicacid (58.0 mg, 0.6 mmol) in H₂O (5.0 mL) was added drop-wise. Themixture was stirred for 1 hour, and then the aqueous phase was extractedwith EtOAc. The combined organic phases were dried over MgSO₄, filteredand evaporated to yield the acid, which was immediately dissolved in DCM(5.0 mL) containing a mixture of allyl chloroformate (48.0 mg, 0.400mmol) and DMAP (48.0 mg, 0.400 mmol, 0.340 mL). The mixture was stirredfor 1 hour and then evaporated to yield the mixed anhydride: MS [M+]calc. 435.0 found 435.9. The anhydride was dissolved in 5.0 mL of EtOHcontaining NH₃ (2.0M), and the mixture was stirred for 18 hours. Thesolvent was evaporated, and the product was purified by flashchromatography eluting with mixtures of hexanes and EtOAc (4:1, 1:1) toyield decarboxylated material (see example 77) and the title product. ¹HNMR (400 MHz, chloroform-D) δ ppm 1.34 (m, 9 H) 6.11 (s, 2 H) 7.41 (s, 1H) 7.49 (d, J=7.62 Hz, 2 H) 7.73 (d, J=8.59 Hz, 1 H) 7.86 (d, J=7.23 Hz,2 H) 8.33 (m, 1 H) 8.49 (s, 1 H); MS [M+H] calc. 354.1 found 354.0.

Example 78 N-1,3-Benzothiazol-5-yl-4-tert-butylbenzamide

See above (example 76). ¹H NMR (400 MHz, DMSO-D₆) δ ppm 1.30 (s, 9 H)7.54 (d, J=8.40 Hz, 2 H) 7.82 (dd, J=8.79, 1.95 Hz, 1 H) 7.90 (d, J=8.59Hz, 2 H) 8.08 (d, J=8.79 Hz, 1 H) 8.59 (d, J=1.95 Hz, 1 H) 9.36 (s, 1H)10.38 (s, 1 H); 1R (neat) 1661 cm⁻¹; MS [M+H] calc. 311.1 found 311.0.

Example 79 4-Chloro-N-[2-(hydroxymethyl)-1,3-benzothiazol-5-yl]benzamide

According to amide bond forming procedure described in Example 2,5-amino-2-methylbenzothiazole reacted with 4-chlorobenzoyl chloride toyield 4-chloro-N-(2-methyl-benzothiazol-5-yl)-benzamide: MS [M+] calc.302, found 302.0. This intermediate was oxidized with SeO₂ to thecorresponding aldehyde as described in Example 70. The aldehyde (3.30mmol) was mixed with NaBH₄ (122 mg, 3.30 mmol) in MeOH (150 mL). Afterthe reaction was complete according to TLC, the volatiles were removedand the residue was dissolved in a mixture of DCM and MeOH (10 mL, 1:5)and passed through a short pad of silica. The filtrate was concentratedand a residue was crystallized from a mixture of EtOAc and MeOH (40:1).A yellow solid formed was collected by filtration. ¹H NMR (400 MHz,DMSO-D6) δ ppm 4.85 (m, 2 H), 6.26 (t, J=5.96 Hz, 1 H), 7.62 (d, J=8.40Hz, 2 H), 7.76 (m, 1 H), 8.02 (m, 3 H), 8.43 (m, 1 H), 10.50 (s, 1 H).MS [M+H] calc. 319.0 found 319.0.

Example 801-(4-chlorophenyl)-N-[2-(hydroxymethyl)-1,3-benzothiazol-5-yl]-5-propyl-1H-pyrazole-4-carboxamide

The title compound was synthesized from 5-amino-2-methylbenzothiazoleand 1-(4-chlorophenyl)-5-propyl-1H-pyrazole-4-carbonyl chlorideaccording to the procedure described in the example 79. ¹H NMR (400 MHz,DMSO-D6) δ ppm 0.76 (t, J=7.32 Hz, 3 H), 1.46 (m, 2 H), 2.97 (m, 2 H),4.85 (d, J=6.05 Hz, 2 H), 6.26 (t, J=5.96 Hz, 1 H), 7.55 (d, J=8.79 Hz,2 1), 7.65 (d, J=8.79 Hz, 2 H), 7.74 (dd, J=8.79, 1.95 Hz, 1 H), 8.01(d, J=8.59 Hz, 1 H), 8.36 (m, 2 H), 10.07 (s, 1 H). MS [M+H) calc. 427.1found 427.0.

Example 811-(4-chlorophenyl)-N-[2-(hydroxymethyl)-1,3-benzothiazol-5-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

The title compound was synthesized from 5-amino-2-methylbenzothiazoleand 1-(4-chlorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonylchloride according to the procedure described in the example 79. ¹H NMR(400 MHz, DMSO-D6) δ ppm 4.86 (d, J=6.05 Hz, 2 H), 6.26 (t, J=5.96 Hz, 1H), 7.60 (d, J=8.59 Hz, 2 H), 7.69 (m, 3 H), 8.04 (d, J=8.59 Hz, 1 H),8.37 (m, J=4.69 Hz, 2 H), 10.72 (s, 1 H). MS [M+H) calc. 453.0 found452.9.

Example 82N-(2,4-dimethyl-1,3-benzothiazol-5-yl)-4-(1-hydroxy-1-methylethyl)benzamide

According to amide bond forming procedure described in Example 1,5-amino-2-methylbenzothiazole reacted with 4-(methoxycarbonyl)benzoicacid to yield N-(2-Methyl-benzothiazol-5-yl)-terephthalamic acid methylester: MS [M+] calc. 326.0, found 326.0. This intermediate was placedinto a flask, which was capped with a rubber septum and charged with N₂gas. THF (10.0 mL) was added, followed by MeMgBr (4.60 mmol, 1.53 mL),and the reaction was stirred for 8 hours at room temperature. Asaturated solution of NH₄Cl was added, and the mixture was evaporated todryness in vacuum. The residue was purified by HPLC eluting withmixtures of MeCN and H₂O containing 1% TFA to yield the title product.1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.62 (s, 6 H) 2.96 (s, 3 H) 3.50(s, 1 H) 7.62 (d, J=8.59 Hz, 2 H) 7.83 (d, J=8.79 Hz, 1 H) 7.90 (d,J=8.59 Hz, 2 H) 8.09 (dd, J=8.79, 1.76 Hz, 2 H) 8.21 (s, 1 H) 8.27 (s, 1H); MMS [M+] cald. 327.1, found 327.0.

Example 834-(Hydroxymethyl)-N-[2-(hydroxymethyl)-1,3-benzothiazol-5-yl]benzamide

According to amide bond forming procedure described in Example 1, allyl(5-amino-1,3-benzothiazol-2-yl)methyl carbonate reacted withp-carboxybenzaldehyde to yield carbonic acid allyl ester5-(4-formyl-benzoylamino)-benzothiazol-2-ylmethyl ester. Thisintermediate (97 mg, 0.25 mmol) and B₁₀H₁₄ (30 mg, 0.25 mmol) werestirred in MeOH (10.0 mL) for 48 hours. The reaction mixture was dilutedwith EtOAc (40.0 mL) and water (30.0 mL) and the organic phaseseparated. The aqueous phase was extracted with EtOAc (2×10.0 mL) andthe combined organic phases were washed with brine solution (30.0 mL).The organic phase was dried with Na₂SO₄, filtered and concentrated invacuum. The residue was purified by silica gel chromatography (1:1EtOAc/hexanes) to yield the title product. ¹H NMR (400 MHz, DMSO-D6) δppm 4.56 (m, 2 H), 4.83 (m, 2 H), 5.32 (t, J=5.66 Hz, 1 H), 6.21 (t,J=5.96 Hz, 1 H), 7.45 (d, J=8.20 Hz, 2 H), 7.76 (dd, J=8.69, 1.86 Hz, 1H), 7.94 (d, J=8.20 Hz, 2 H), 7.99 (d, J=8.59 Hz, 1 H), 8.42 (d, J=1.76Hz, 1 H), 10.35 (s, 1 H). MS [M+H) calc. 315.1 found 315.0.

Example 844-tert-butyl-N-(4-cyano-2-methyl-1,3-benzothiazol-5-yl)benzamide

N-(4-Bromo-2-methyl-1,3-benzothiazol-5-yl)-4-tert-butylbenzamide(example 12) (50.0 mg, 0.124 mmol) and CuCN (22 mg, 0.248 mmol) weredissolved in DMF (3.00 mL) and heated to 250° C. in a microwave oven for20 minutes. The mixture was cooled, and the solvent was evaporated. Theresidue was purified by flash chromatography on silica gel eluting withmixtures of hexanes and EtOAc (4:1, 2:1, 1:1) to yield the titleproduct. ¹H NMR (400 MHz, chloroform-D) δ ppm 1.36 (s, 9 H) 2.92 (s, 3H) 7.55 (ddd, J=8.74, 2.25, 2.10 Hz, 2 H) 7.92 (ddd, J=8.64, 2.25,2.00.Hz, 2 H) 8.03. (d; J=8.98 Hz, 1 H) 8.58 (s, 1 H) 8.69 (m, 1H); MS[M+] calcd. 350.1, found 350.0.

Example 854-tert-butyl-N-[2-(hydroxymethyl)-1,3-benzoxazol-5-yl]benzamide

A solution of 2-methyl-5-nitro-1,3-benzoxazole (500 mg, 2.8 mmol) in(dimethoxymethyl)dimethylamine (5.0 ml) was stirred in the microwave at200° C. for 15 min. (900 sec.). The precipitate was filtered off, washedwith methanol and dried yielding(E)-N,N-dimethyl-2-(5-nitro-1,3-benzoxazol-2-yl)ethylenamine, 200 mg(31%), as a yellow powder. ¹H NMR (400 MHz, DMSO-D6) δ ppm 2.72-3.20 (m,6 H) 5.02 (d, J=13.08 Hz, 1 H) 7.59 (d, J=8.79 Hz, 1 H) 7.74 (d, J=13.08Hz, 1 H) 8.00 (dd, J=8.79, 2.34 Hz, 1 H) 8.10 (d, J=2.34 Hz, 1 H).

(E)-N,N-Dimethyl-2-(5-nitro-1,3-benzoxazol-2-yl)ethylenamine (200 mg,0.86 mmol) dissolved in methanol (20 ml), was hydrogenated over 10%palladium on carbon (500 mg) for 1 hour. The catalyst was removed viafiltration through Celite and the filtrate was concentrated to yield acrude 2-[(E)-2-(dimethylamino)vinyl]-1,3-benzoxazol-5-amine, 120 mg(69%), which used as such in the next reaction step. ¹H NMR (400 MHz,DMSO-D6) δ ppm 2.88 (s, 6 H) 4.76 (s, 2 H) 4.88 (d, J=13.28 Hz, 1 H)6.31 (dd, J=8.50, 2.25 Hz, 1 H) 6.54 (d, J=2.25 Hz, 1 H) 7.02 (d, J=8.50Hz, 1 H) 7.48 (d, J=13.28 Hz, 1 H).

2-[(E)-2-(Dimethylamino)vinyl]-1,3-benzoxazol-5-amine (100 mg, 0.49mmol) was dissolved in DCM (5.0 ml) containing dimethylaminopyridine(179 mg, 0.74 mmol). 4-tert-Butylbenzoyl chloride (144mg, 1.47 mmol) wasadded and the mixture was stirred at ambient temperature for 1 h. Themixture was diluted with DCM and extracted with water. The organic phasewas dried over anhydrous sodium sulphate, and concentrated under reducedpressure. The residue was purified on a small silica gel column usingethyl acetate as the eluent to yield4-tert-butyl-N-{2-[(E)-2-(dimethylamino)vinyl]1,3-benzoxazol-5-yl)benzamide,45 mg (25%). ¹H NMR (400 MHz, methanol-D4) δ ppm 1.37 (s, 9 H) 2.99 (s,6 H) 5.02 (d, J=13.28 Hz, 1 H) 7.29-7.35 (m, 1 H) 7.35-7.44 (m, 1 H)7.51-7.57 (m, 2 H) 7.63 (d, J=13.28 Hz, 1 H) 7.78 (d, J=1.95 Hz, 1 H)7.83-7.93 (m, 2 H).

4-tert-Butyl-N-{2-[(E)-2-(dimethylamino)vinyl]-1,3-benzoxazol-5-yl}benzamide.(45 mg, 0.124 mmol) was dissolved in a mixture of THF and water (1:1, 10ml) and sodium periodate (158 mg, 0.74 mmol) was added. The mixture wasstirred at ambient temperature for 3 h. The solution was extracted withDCM, the organic phase was dried over anhydrous sodium sulphate andconcentrated under reduced pressure. The residue was dissolved inmethanol (20 ml) and treated with sodium borohydride (200 mg, 5.4 mmol)at ambient temperature for 1 h. The reaction mixture was diluted withwater and extracted with dichloromethane. The organic phase was driedover anhydrous sodium sulphate and concentrated under reduced pressure.The residue was purified by a column chromatography on silicagel using50% ethyl acetate in hexane as an eluent to yield the title product, 18mg (45%) as colourless oil. ¹H NMR (400 Mz, methanoL-D4) δ ppm 1.35 (s,9 H) 4.79 (s, 2 H) 7.45-7.64 (m, 3 H) 7.61-7.73 (m, 1 H) 7.80-7.96 (m, 2H) 8.12 (d, J=1.76 Hz, 1 H). MS [M+] calcd. 325.2, found 325.0.

Example 86 5-(4-tert-butylbenzoylamino)-1,3-benzothiazol-2-ylcarboxylicacid

A solution of 4-tert-butyl-N-(2-formyl-1,3-benzothiazol-5-yl)-benzamide(0.1 mmol) in THF (2 mL) was treated sequentially with a solution ofsulfamic acid (0.2 mmol) in water (0.5 mL) and a solution of sodiumchlorite (0.15 eq) in water (0.5 mL). The mixture was stirred at ambienttemperature for 1 h, then partitioned between ethyl acetate (5 mL ) andwater (5 mL). The organic phase was separated, the water phase wasextracted 3 times with ethyl acetate. Combined organic phase was driedover anhydrous sodium sulphate and concentrated in vacuo. The crudematerial was purified by preparative HPLC (X-Terra C8 column, 19×300mm), using a gradient of A (water 95%, containing NH₄OAc (0.01 M), and5% acetonitrile) and B (acetonitrile), to give the title compound. MS[M+] calcd. 354.4, found 355.0

Example 874-tert-Butyl-N-(2-methoxycarbonyl-1,3-benzothiazol-5-yl)-benzamide

A solution of 5-(4-tert-butylbenzoylamino)-1,3-benzothiazol-2-ylcarboxylic acid (0.1 mmol) in methanol (3 mL) was treated with one dropof concentrated hydrochloric acid. The mixture was concentrated todryness in vacuo. The oily residue was then purified by preparative HPLC(X-Terra C8 column, 19×300 mm), using a gradient of A (water 95%,containing NH₄OAc (0.01 M), and 5% acetonitrile) and B (acetonitrile),to give the title compound as a solid. ¹H NMR (400 MHz, DMSO-d6) δ 1.32(s, 9 H), 3.65 (s, 1H), 7.25 (d, J=8.6 Hz, 2 H), 7.65-7.79 (m, 2H), 7.85(d, J=8.6 Hz; 1 H), 7.9.1 .(s, 1 H), 8.29 (s, 1 H). MS [M+] calcd.368.5, found 369

Pharmacology

1. hVR1 FLIPR (Fluorometric Image Plate Reader) Screening Assay

Transfected CHO cells, stably expessing hVR1 (15,000 cells/well) areseeded in 50 ul media in a black clear bottom 384 plate (Greiner) andgrown in a humidified incubator (37° C., 2% CO₂), 24-30 hours prior toexperiment.

Subsequently, the media is removed from the cell plate by inversion and2 μM Fluo-4 is added using a multidrop (Labsystems). Following the 40minutes dye incubation in the dark at 37° C. and 2% CO₂, theextracellular dye present is washed away using an EMBLA (Scatron),leaving the cells in 40 ul of assay buffer (1×HBSS, 10 mM D-Glucose, 1mM CaCl₂, 10 mM HEPES, 10×7.5% NaHCO₃ and 2.5 mM Probenecid).

FLIPR Assay—IC₅₀ Determination Protocol

For IC₅₀ determinations the fluorescence is read using FLIPR filter 1(em 520-545 nM). A cellular baseline recording is taken for 30 seconds,followed by a 20 μl addition of 10, titrated half-log concentrations ofthe test compound, yielding cellular concentration ranging from 3 μM to0.1 nM. Data is collected every 2 seconds for a further 5 minutes priorto the addition of a VR1 agonist solution: either 50 nM solution ofcapsaicin or MES (2-[N-morpholino) ethanesulfonic acid) buffer (pH 5.2),by the FLIPR pipettor. The FLIPR continues to collect data for a further4 minutes. Compounds having antagonistic properties against the hVR1will inhibit the increase in intracellular calcium in response to thecapsaicin addition. This consequently leading to a reduction influorescence signal and providing a reduced fluorescence reading,compared with no compound, buffer controls. Data is exported by theFLIPR program as a sum of fluorescence calculated under the curve uponthe addition of capsaicin. Maximum inhibition, Hill slope and IC₅₀ datafor each compound are generated.

2. DRGs were dissected out from adult Sprague Dawley rats (100-300 gr),and placed on ice in L15 Leibovitz medium. The ganglia were enzymetreated with Collagenase 80 U/ml+. Dispase 34 U/ml dissolved in DMEM +5%serum, overnight at 37 ° C. The next day, cells were triturated withfire polished pasteur pipettes, and seeded in the center of 58 mmdiameter Nunc cell dishes coated with Poly-D Lysine (1 mg/mL). The DRGswere cultured in a defined medium without foetal bovine serum,containing Dulbecco's MEM/NUT MIX F-12 (1:1) without L-glutamine butwith pyridoxine, 6 mg/mL D(+)-Glucose, 100 μg/mL apo-transferrin, 1mg/mL BSA, 20 μg/mL insulin, 2 mM L-glutamine, 50 IU/mL Penicillin, 50μg/mL Streptomycin and 0.01 μg/mL NGF-7S.

When the cells had grown for 2 days up to 4 weeks, the experiments weredone. Cells were chosen based on size and presence of neurites. Smallcells with long processes were used for recording (most likely to be Cneurons, with native VR1 receptors).

The cells were recorded with conventional whole cell voltage clamp patchclamp, using the following solutions (calcium ion free):

The extracellular solution comprised (in mM): NaCl 137, KCl 5, MgCl₂*H₂O1.2, HEPES 10, Glucose 10, EGTA 5, Sucrose 50, pH to 7.4 with NaOH.

The intracellular solution comprised K-gluconate 140, NaCl 3, MgCl₂*H₂O1.2, HEPES 10, EGTA 1, pH to 7.2 with KOH. When the cells werepenetrated with suction, a puff of capsaicin (500 nM) was used todetermine if the cell expressed VR1 receptor. If not, a new cell waschosen. If yes, then the compounds were added in increasing doses beforethe capsaicin pulse (500 nM), to determine an IC₅₀ value.

List of Abbreviations

-   VR1 vanilloid receptor 1-   IBS irritable bowel syndrome-   IBD inflammatory bowel disease-   GERD gastro-esophageal reflux disease-   DRG Dorsal Root Ganglion-   BSA Bovine Serum Albumin-   HEPES 4-(2-Hydroxyethyl)piperazine-1-ethanesulfonic acid-   EGTA Ethylene glycol-bis(2-aminoethylether)-N,N,N′,N′-tetraacetic    acid-   DMEM Dulbeccos Modified Eagle's Medium

Results

Typical IC₅₀ values as measured in the assays described above are 10 μMor less. In one aspect of the invention the IC₅₀ is below 500 nM. Inanother aspect of the invention the IC₅₀ is below 100 nM. In a furtheraspect of the invention the IC₅₀ is below 10 nM.

Results from the hVR1 FLIPR Example No. IC₅₀ nM (agonist) 2 10(capsaicin) 60 (H⁺/MES buffer) 71 200 (capsaicin)  19 50 (capsaicin) 45(H⁺/MES buffer)

1-20. (canceled)
 21. A compound having the formula I

wherein: ring P is C₆₋₁₀aryl, C₃₋₇cycloalkyl, C₅₋₆-heteroaryl, whichring P may be fused with phenyl, C₅₋₆-heteroaryl, C₃₋₇cycloalkyl orC₃₋₇heterocycloalkyl; R¹ is NO₂, NH₂, halo, N(C₁₋₆alkyl)₂, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, C₁₋₆haloalkylO,phenylC₀₋₆alkyl, C₅₋₆heteroarylC₀₋₆alkyl, C₃₋₇cycloalkylC₀₋₆alkyl,C₃₋₇heterocycloalkylC₀₋₆alkyl, C₁₋₆alkylOC₀₋₆alkyl, C₁₋₆alkylSC₀₋₆alkylor C₁₋₆alkylNC₀₋₆alkyl; n is 1, 2, 3, 4 or 5; X is O, S or N; R⁴ is H,C₁₋₄alkyl, hydroxyC₁₋₆alkyl or C₁₋₆alkylOC₁₋₆alkyl, or is absent when Xis N; R³ is H, C₁₋₆alkyl, C₁₋₆haloalkyl, R⁵OC₁₋₆alkyl, R⁵O(CO), R⁵CO,NR⁵R⁶CO, NR⁵R⁶C₀₋₆alkyl, C₂₋₆alkenylOC₀₋₆alkyl or hydroxyC₁₋₆alkyl; R⁵and R⁶ are at each occurrence independently selected from H, C₁₋₆alkyl,C₆₋₁₀aryl, C₅₋₆heteroaryl, C₁₋₄alkylSO₂ and C₁₋₃alkylCO; R⁷ and R⁸ areindependently selected from H, C₁₋₆alkyl, halo, cyano,C₁₋₆alkylOC₀₋₆alkyl, OH, NO₂ and COR⁹, N(R⁹)₂; and R⁹ is H or C₁₋₆alkyl;wherein any alkyl, alkylOalkyl, haloalkyl, haloalkylO, phenyl,heteroaryl, cycloalkyl or heterocycloalkyl group may be substituted withone or more A, where A at each occurrence is independently selected fromOH, NO₂, R⁹CO, R⁹O(CO), N(R⁹)₂, R⁹S, R⁹SO₂, halo or C₁₋₆alkylOC₀₋₆alkyl,or a salt, solvate or solvated salt thereof.
 22. A compound according toclaim 21, wherein: X is N; R³ is H, C₁₋₆alkyl, C₁₋₆iodoalkyl,C₁₋₆bromoalkyl, C₁₋₆chloroalkyl, C₁₋₆alkylOC₀₋₆alkyl, R⁵OC₁₋₆alkyl,R⁵CO, R⁵CO₂, NR⁵R⁶CO, NR⁵R⁶C₀₋₆alkyl or C₂₋₆alkenylOC₀₋₆alkyl; and R⁴ isH, C₁₋₄alkyl, hydroxyC₁₋₆alkyl or C₁₋₆alkylOC₁₋₆alkyl.
 23. A compoundaccording to claim 21, wherein: X is N; R³ is C₁₋₆fluoroalkyl orhydroxyC₁₋₂alkyl, and R⁴ is H.
 24. A compound according to claim 21,wherein: X is O or S; R³ is H, C₁₋₆alkyl, C₁₋₆haloalkyl, R⁵OC₁₋₆alkyl,R⁵O(CO), R⁵CO, NR⁵R⁶CO, NR⁵R⁶C₀₋₆alkyl, C₂₋₆alkenylOC₀₋₆alkyl orhydroxyC₁₋₆alkyl, and R⁴ is absent.
 25. A compound according to claim21, wherein: ring P is C₆₋₁₀aryl, C₅₋₆heteroaryl, which ring P may befused with C₃₋₇heterocycloalkyl; R¹ is NO₂, NH₂, halo, N(C₁₋₆alkyl)₂,C₁₋₆alkyl, C₂₋₆alkenyl, C₁₋₆haloalkyl, C₁₋₆haloalkylO, phenylC₀₋₆alkyl,C₃₋₇heterocycloalkylC₀₋₆alkyl, C₁₋₆alkylOC₀₋₆alkyl orC₁₋₆alkylSC₀₋₆alkyl; n is 1, 2 or 3; X is O, N or S; R⁴ is C₁₋₄alkyl orhydroxyC₁₋₆alkyl, or is absent when X is N; R³ is C₁₋₆alkyl, NR⁵R⁶CO,NR⁵R⁶C₀₋₆alkyl, C₂₋₆alkenylOC₀₋₆alkyl or hydroxyC₁₋₆alkyl; R⁵ and R⁶ areindependently selected from H, C₆₋₁₀aryl, C₅₋₆heteroaryl, C₁₋₄alkylSO₂and C₁₋₃alkylCO; R⁷ and R⁸ are independently selected from H, halo andcyano and wherein: any alkyl, phenyl, heteroaryl group may besubstituted with one or more A where A at each occurrence isindependently selected from OH, NO₂, halo or C₁₋₆alkylOC₀₋₆alkyl.
 26. Acompound according to claim 25, wherein: X is N; R³ is H or C₁₋₆alkyl;and R⁴ is H.
 27. A compound according to claim 25, wherein: X is N; R³is C₁₋₆fluoroalkyl and R⁴ is H.
 28. A compound according to claim 21,wherein X is S and R³is methyl.
 29. A compound according to claim 21,wherein X is O and R³ is C₁₋₆alkyl or hydroxyC₁₋₆alkyl.
 30. A compoundaccording to claim 21, wherein X is N, R³ is C₁₋₆alkyl and R⁴ isC₁₋₆alkyl or hydroxyC₁₋₆alkyl.
 31. A compound according to claim 21,wherein: ring P is phenyl, and R¹ is NO₂, NH₂, halo, N(C₁₋₆alkyl)₂,C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, C₁₋₆haloalkylO,phenylC₀₋₆alkyl, C₅₋₆heteroarylC₀₋₆alkyl, C₃₋₇cycloalkylC₀₋₆alkyl,C₃₋₇heterocycloalkylC₀₋₆alkyl, C₁₋₆alkylOC₀₋₆alkyl, C₁₋₆alkylSC₀₋₆alkylor C₁₋₆alkylNC₀₋₆alkyl optionally substituted with one or more A.
 32. Acompound according to claim 21, wherein ring P is pyrazolyl, pyridine,benzdioxolane, furan, thiophene or naphthalene.
 33. A compound accordingto claim 21, selected from the group consisting of:4-tert-Butoxy-N-[2-(hydroxymethyl)-1,3-benzothiazol-5-yl]benzamide;4-Bromo-N-[2-(hydroxymethyl)-1,3-benzothiazol-5-yl]benzamide;N-[2-(Hydroxymethyl)-1,3-benzothiazol-5-yl]-4-iodobenzamide;N-[2-(Hydroxymethyl)-1,3-benzothiazol-5-yl]-4-morpholin-4-ylbenzamide;N-{2-[(Allyloxy)methyl]-1,3-benzothiazol-5-yl}-4-morpholin-4-ylbenzamide;N-[2-(Hydroxymethyl)-1,3-benzothiazol-5-yl]-1-phenyl-5-propyl-1H-pyrazole-4-carboxamide;1-tert-Butyl-N-[2-(hydroxymethyl)-1,3-benzothiazol-5-yl]-3-methyl-1H-pyrazole-5-carboxamide;4-(Ethoxymethyl)-N-[2-(hydroxymethyl)-1,3-benzothiazol-5-yl]benzamide;N-[2-(Hydroxymethyl)-1,3-benzothiazol-5-yl]-1-phenyl-1H-pyrazole-5-carboxamide;4-Bromo-N-[2-(hydroxymethyl)-1,3-benzothiazol-5-yl]-2-methylbenzamide;4-tert-Butoxy-N-(2-methyl-1,3-benzoxazol-5-yl) benzamide;N-(4-Bromo-2-methyl-1,3-benzothiazol-5-yl)-4-tert-butylbenzamide;4-tert-Butyl-N-(4,7-dibromo-2-methyl-1,3-benzothiazol-5-yl)benzamide;N-[2-(Hydroxymethyl)-1,3-benzothiazol-5-yl]-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;4-Iodo-N-(2-methyl-5-benzothiazolyl)benzamide;4-(tert-Butoxymethyl)-N-[2-(hydroxymethyl)-1,3-benzothiazol-5-yl]benzamide;N-( 1,2-Dimethyl-1H-benzimidazol-5-yl)-4-iodobenzamide;N-[2-(Hydroxymethyl)-1,3-benzothiazol-5-yl]-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzamide;N-[2-(Hydroxymethyl)-1,3-benzothiazol-5-yl]-4-isopropoxybenzamide;4-Bromo-2-chloro-N-[2-(hydroxymethyl)-1,3-benzothiazol-5-yl]benzamide;4-Bromo-2-fluoro-N-[2-(hydroxymethyl)-1,3-benzothiazol-5-yl]benzamide;N-[2-(Hydroxymethyl)-1,3-benzothiazol-5-yl]-4-(morpholin-4-ylmethyl)benzamide;3-Fluoro-N-[2-(hydroxymethyl)-1,3-benzothiazol-5-yl]-4-(trifluoromethyl)benzamide;4-tert-Butoxy-N-[4-chloro-2-(hydroxymethyl)-1,3-benzothiazol-5-yl]benzamide;4-(tert-Butoxymethyl)-N-[4-chloro-2-(hydroxymethyl)-1,3-benzothiazol-5-yl]benzamide;3-Fluoro-N-(2-methyl-1,3-benzothiazol-5-yl)-4-trifluoromethyl-benzamide;2-tert-Butyl-5-methyl-2H-pyrazole-3-carboxylic acid(2-methyl-1,3-benzothiazol-5-yl)-amide;2-Fluoro-N-(2-methyl-1,3-benzothiazol-5-yl)-4-trifluoromethyl-benzamide;2-Fluoro-N-(2-methyl-1,3-benzothiazol-5-yl)-3-trifluoromethyl-benzamide;4-Fluoro-N-(2-methyl-1,3-benzothiazol-5-yl)-3-trifluoromethyl-benzamide;3,4-Dimethyl-N-(2-methyl-benzothiazol-5-yl)-benzamide;2,2-Difluoro-benzo[1,3]dioxole-5-carboxylic acid(2-methyl-1,3-benzothiazol-5-yl)-amide;N-(2-Methyl-1,3-benzothiazol-5-yl)-6-trifluoromethyl-nicotinamide;N-(2-Methyl-1,3-benzothiazol-5-yl)-4-propyl-benzamide;3-Iodo-N-(2-methyl-1,3-benzothiazol-5-yl)-benzamide;2,5-Dimethyl-furan-3-carboxylic acid(2-methyl-1,3-benzothiazol-5-yl)-amide;5-tert-Butyl-2-methyl-furan-3-carboxylic acid(2-methyl-1,3-benzothiazol-5-yl)-amide;4-Bromo-3-methyl-N-(2-methyl-1,3-benzothiazol-5-yl)-benzamide;3,4-Difluoro-N-(2-methyl-1,3-benzothiazol-5-yl)-benzamide;3-Chloro-2-fluoro-N-(2-methyl-1,3-benzothiazol-5-yl)-benzamide;Pyridine-2-carboxylic acid (2-methyl-1,3-benzothiazol-5-yl)-amide;2-Benzyl-5-tert-butyl-2H-pyrazole-3-carboxylic acid(2-methyl-1,3-benzothiazol-5-yl)-amide;3-Fluoro-4-trifluoromethyl-N-(2-trifluoromethyl-1H-benzimidazol-5-yl)-benzamide;2-Fluoro-5-trifluoromethyl-N-(2-trifluoromethyl-1H-benzimidazol-5-yl)-benzamide;4-Chloro-N-(2-methyl-benzothiazol-5-yl)-benzamide;1-Phenyl-5-trifluoromethyl-1H-pyrazole-3-carboxylic acid(2-methyl-1,3-benzothiazol-5-yl)-amide;1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid(2-methyl-1,3-benzothiazol-5-yl)-amide;2,3-Difluoro-N-(2-methyl-1,3-benzothiazol-5-yl)-4-trifluoromethyl-benzamide;3-Fluoro-4-methyl-N-(2-methyl-1,3-benzothiazol-5-yl)-benzamide;4-tert-Butyl-N-(2-methyl-1,3-benzothiazol-5-yl)-benzamide;4-Ethyl-N-(2-methyl-1,3-benzothiazol-5-yl)-benzamide;4-tert-Butyl-N-(2-methyl-1,3-benzooxazol-5-yl)-benzamide;Biphenyl-4-carboxylic acid (2-methyl-1,3-benzothiazol-5-yl)-amide;3-Bromo-thiophene-2-carboxylic acid(2-methyl-1,3-benzothiazol-5-yl)-amide;4-Bromo-2-methyl-N-(2-methyl-1,3-benzothiazol-5-yl)-benzamide;4-tert-Butoxy-N-(2-methyl-1,3-benzothiazol-5-yl)-benzamide;2-Chloro-3,4-dimethoxy-N-(2-methyl-1,3-benzothiazol-5-yl)-benzamide;4-Iodo-N-(2-methyl-1,3-benzothiazol-5-yl)-benzamide;4-Amino-N-(2-methyl-1,3-benzothiazol-5-yl)-3-nitro-benzamide;N-(2-Methyl-1,3-benzothiazol-5-yl)-4-vinyl-benzamide;4-Ethoxy-N-(2-methyl-1,3-benzothiazol-5-yl)-benzamide;4-Ethylsulfanyl-N-(2-methyl-1,3-benzothiazol-5-yl)-benzamide;4-Dimethylamino-naphthalene-1-carboxylic acid(2-methyl-1,3-benzothiazol-5-yl)-amide;2-Fluoro-6-iodo-N-(2-methyl-1,3-benzothiazol-5-yl)-benzamide;4-Ethoxymethyl-N-(2-methyl-1,3-benzothiazol-5-yl)-benzamide;N-(2-Methyl-1,3-benzothiazol-5-yl)-4-trifluoromethoxy-benzamide;4-Chloro-3-fluoro-N-(2-methyl-1,3-benzothiazol-5-yl)-benzamide;4-tert-Butyl-N-(2-formyl-1,3-benzothiazol-5-yl)-benzamide;4-tert-Butyl-N-(2-hydroxymethyl-1,3-benzothiazol-5-yl)-benzamide;4-tert-Butyl-N-(2-{[(2-methoxypyridin-3-yl)amino]methyl}-1,3-benzothiazol-5-yl)benzamide;4-tert-Butyl-N-[2-( 1-hydroxyethyl)-1,3-benzothiazol-5-yl]benzamide;4-tert-Butyl-N-{2-[(1H-pyrazol-3-ylamino)methyl]-1,3-benzothiazol-5-yl}benzamide;4-(1,1-Dimethylethyl)-N-[2-[[(4-nitrophenyl)amino]methyl]-5-benzothiazolyl]-benzamide;N-[2-(Aminomethyl)-1,3-benzothiazol-5-yl]-4-tert-butylbenzamide;4-tert-Butyl-N-(2-{[(methylsulfonyl)amino]methyl}-1,3-benzothiazol-5-yl)benzamide;N-{2-[(Acetylamino)methyl]-1,3-benzothiazol-5-yl}-4-tert-butylbenzamide;5-[(4-tert-Butylbenzoyl)amino]-1,3-benzothiazole-2-carboxamide;N-1,3-Benzothiazol-5-yl-4-tert-butylbenzamide;4-Chloro-N-[2-(hydroxymethyl)-1,3-benzothiazol-5-yl]benzamide;1-(4-chlorophenyl)-N-[2-(hydroxymethyl)-1,3-benzothiazol-5-yl]-5-propyl-1H-pyrazole-4-carboxamide;1-(4-Chlorophenyl)-N-[2-(hydroxymethyl)-1,3-benzothiazol-5-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;N-(2,4-Dimethyl-1,3-benzothiazol-5-yl)-4-(1-hydroxy-1-methylethyl)benzamide;4-(Hydroxymethyl)-N-[2-(hydroxymethyl)-1,3-benzothiazol-5-yl]benzamide;4-tert-Butyl-N-(4-cyano-2-methyl-1,3-benzothiazol-5-yl)benzamide;4-tert-Butyl-N-[2-(hydroxymethyl)-1,3-benzoxazol-5-yl]benzamide;5-(4-tert-Butylbenzoylamino)-1,3-benzothiazol-2-ylcarboxylic acid, and4-tert-Butyl-N-(2-methoxycarbonyl-1,3-benzothiazol-5-yl)-benzamide; or asalt, solvate or solvated salt thereof.
 34. A pharmaceutical compositioncomprising as an active ingredient a therapeutically effective amount ofcompound having the formula I

wherein: ring P is C₆₋₁₀aryl, C₃₋₇cycloalkyl, C₅₋₆heteroaryl, which ringP may be fused with phenyl, C₅₋₆heteroaryl, C₃₋₇cycloalkyl orC₃₋₇heterocycloalkyl; R¹ is NO₂, NH₂, halo, N(C₁₋₆alkyl)₂, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, C₁₋₆haloalkylO,phenylC₀₋₆alkyl, C₅₋₆heteroarylC₀₋₆alkyl, C₃₋₇cycloalkylC₀₋₆alkyl,C₃₋₇heterocycloalkylC₀₋₆alkyl, C₁₋₆alkylOC₀₋₆alkyl, C₁₋₆alkylSC₀₋₆alkylor C₁₋₆alkylNC₀₋₆alkyl n is 1,2, 3, 4 or 5; X is O, S or N; R⁴ is H,C₁₋₄alkyl, hydroxyC₁₋₆alkyl or C₁₋₆alkylOC₁₋₆alkyl, or is absent when Xis N; R³ is H, C₁₋₆alkyl, C₁₋₆haloalkyl, R⁵OC₁₋₆alkyl, R⁵O(CO), R⁵CO,NR⁵R⁶CO, NR⁵R⁶C₀₋₆alkyl, C₂₋₆alkenylOC₀₋₆alkyl or hydroxyC₁₋₆alkyl; R⁵and R⁶ are at each occurrence independently selected from H, C₁₋₆alkyl,C₆₋₁₀aryl, C₅₋₆heteroaryl, C₁₋₄alkylSO₂ and C₁₋₃alkylCO; R⁷ and R⁸ areindependently selected from H, C₁₋₆alkyl, halo, cyano,C₁₋₆alkylOC₀₋₆alkyl, OH, NO₂ and COR⁹, N(R⁹)₂; and R⁹ is H or C₁₋₆alkyl;wherein any alkyl, alkylOalkyl, haloalkyl, haloalkylO, phenyl,heteroaryl, cycloalkyl or heterocycloalkyl group may be substituted withone or more A, where A at each occurrence is independently selected fromOH, NO₂, R⁹CO, R⁹O(CO), N(R⁹)₂, R⁹S, R⁹SO₂, halo or C₁₋₆alkylOC₀₋₆alkyl,or a salt, solvate or solvated salt thereof, in association with one ormore pharmaceutically acceptable diluents, excipients or inert carriers.35. A method of treating VR1 mediated disorders, acute and chronic paindisorders, acute and chronic neuropathic pain or acute and chronicinflammatory pain comprising administering a therapeutically effectiveamount of a pharmaceutical composition according to claim
 34. 36. Amethod of treatment of VR1 mediated disorders, acute and chronic paindisorders, acute and chronic neuropathic pain, acute or chronicinflammatory pain, or respiratory diseases, comprising administering toa mammal a therapeutically effective amount of compound having theformula I

wherein: ring P is C₆₋₁₀aryl, C₃₋₇cycloalkyl, C₅₋₆heteroaryl, which ringP may be fused with phenyl, C₅₋₆heteroaryl, C₃₋₇cycloalkyl orC₃₋₇heterocycloalkyl; R¹ is NO₂, NH₂, halo, N(C₁₋₆alkyl)₂, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, C₁₋₆haloalkylO,phenylC₀₋₆alkyl, C₅₋₆heteroarylC₀₋₆alkyl, C₃₋₇cycloalkylC₀₋₆alkyl,C₃₋₇heterocycloalkylC₀₋₆alkyl, C₁₋₆alkylOC₀₋₆alkyl, C₁₋₆alkylSC₀₋₆alkylor C₁₋₆alkylNC₀₋₆alkyl; n is 1,2,3,4 or 5; X is O, S or N; R⁴ is H,C₁₋₄alkyl, hydroxyC₁₋₆alkyl or C₁₋₆alkylOC₁₋₆alkyl, or is absent when Xis N; R³ is H, C₁₋₆alkyl, C₁₋₆haloalkyl, R⁵OC₁₋₆alkyl, R⁵O(CO), R⁵CO,NR⁵R⁶CO, NR⁵R⁶C₀₋₆alkyl, C₂₋₆alkenylOC₀₋₆alkyl or hydroxyC₁₋₆alkyl; R⁵and R⁶ are at each occurrence independently selected from H, C₁₋₆alkyl,C₆ ₁₀aryl, C₅₋₆heteroaryl, C₁₋₄alkylSO₂ and C₁₋₃alkylCO; R⁷ and R⁸ areindependently selected from H, C₁₋₆alkyl, halo, cyano,C₁₋₆alkylOC₀₋₆alkyl, OH, NO₂ and COR⁹, N(R⁹)₂; and R⁹ is H or C₁₋₆alkyl;wherein any alkyl, alkylOalkyl, haloalkyl, haloalkylO, phenyl,heteroaryl, cycloalkyl or heterocycloalkyl group may be substituted withone or more A, where A at each occurrence is independently selected fromOH, NO₂, R⁹CO, R⁹O(CO), N(R⁹)₂, R⁹S, R⁹SO₂, halo or C₁₋₆alkylOC₀₋₆alkyl,or a salt, solvate or solvated salt thereof.
 37. The method according toclaim 36 wherein said mammal is a human.
 38. A compound selected fromthe group consisting of Allyl (5-amino-1,3-benzothiazol-2-yl)methylcarbonate; 4-tert-Butyl-N-(2-formyl-1,3-benzothiazol-5-yl)-benzamide;4-Bromo-2-methyl-benzothiazol-5-ylamine, and4-Chloro-2-methyl-benzothiazole-5-ylamine.
 39. A pharmaceuticalcomposition comprising as an active ingredient a therapeuticallyeffective amount of the group consisting of:4-tert-Butoxy-N-[2-(hydroxymethyl)-1,3-benzothiazol-5-yl]benzamide;4-Bromo-N-[2-(hydroxymethyl)-1,3-benzothiazol-5-yl]benzamide;N-[2-(Hydroxymethyl)-1,3-benzothiazol-5-yl]-4-iodobenzamide;N-[2-(Hydroxymethyl)-1,3-benzothiazol-5-yl]-4-morpholin-4-ylbenzamide;N-{2-[(Allyloxy)methyl]-1,3-benzothiazol-5-yl}-4-morpholin-4-ylbenzamide;N-[2-(Hydroxymethyl)-1,3-benzothiazol-5-yl]-1-phenyl-5-propyl-1H-pyrazole-4-carboxamide;1-tert-Butyl-N-[2-(hydroxymethyl)-1,3-benzothiazol-5-yl]-3-methyl-1H-pyrazole-5-carboxamide;4-(Ethoxymethyl)-N-[2-(hydroxymethyl)-1,3-benzothiazol-5-yl]benzamide;N-[2-(Hydroxymethyl)-1,3-benzothiazol-5-yl]-1-phenyl-1H-pyrazole-5-carboxamide;4-Bromo-N-[2-(hydroxymethyl)-1,3-benzothiazol-5-yl]-2-methylbenzamide;4-tert-Butoxy-N-(2-methyl-1,3-benzoxazol-5-yl)benzamide;N-(4-Bromo-2-methyl-1,3-benzothiazol-5-yl)-4-tert-butylbenzamide;4-tert-Butyl-N-(4,7-dibromo-2-methyl-1,3-benzothiazol-5-yl)benzamide;N-[2-(Hydroxymethyl)-1,3-benzothiazol-5-yl]-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;4-Iodo-N-(2-methyl-5-benzothiazolyl)benzamide;4-(tert-Butoxymethyl)-N-[2-(hydroxymethyl)-1,3-benzothiazol-5-yl]benzamide;N-( 1,2-Dimethyl-1H-benzimidazol-5-yl)-4-iodobenzamide;N-[2-(Hydroxymethyl)-1,3-benzothiazol-5-yl]-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzamide;N-[2-(Hydroxymethyl)-1,3-benzothiazol-5-yl]-4-isopropoxybenzamide;4-Bromo-2-chloro-N-[2-(hydroxymethyl)-1,3-benzothiazol-5-yl]benzamide;4-Bromo-2-fluoro-N-[2-(hydroxymethyl)-1,3-benzothiazol-5-yl]benzamide;N-[2-(Hydroxymethyl)-1,3-benzothiazol-5-yl]-4-(morpholin-4-ylmethyl)benzamide;3-Fluoro-N-[2-(hydroxymethyl)-1,3-benzothiazol-5-yl]-4-(trifluoromethyl)benzamide;4-tert-Butoxy-N-[4-chloro-2-(hydroxymethyl)-1,3-benzothiazol-5-yl]benzamide;4-(tert-Butoxymethyl)-N-[4-chloro-2-(hydroxymethyl)-1,3-benzothiazol-5-yl]benzamide;3-Fluoro-N-(2-methyl-1,3-benzothiazol-5-yl)-4-trifluoromethyl-benzamide;2-tert-Butyl-5-methyl-2H-pyrazole-3-carboxylic acid(2-methyl-1,3-benzothiazol-5-yl)-amide;2-Fluoro-N-(2-methyl-1,3-benzothiazol-5-yl)-4-trifluoromethyl-benzamide;2-Fluoro-N-(2-methyl-1,3-benzothiazol-5-yl)-3-trifluoromethyl-benzamide;4-Fluoro-N-(2-methyl-1,3-benzothiazol-5-yl)-3-trifluoromethyl-benzamide;3,4-Dimethyl-N-(2-methyl-benzothiazol-5-yl)-benzamide;2,2-Difluoro-benzo[1,3]dioxole-5-carboxylic acid(2-methyl-1,3-benzothiazol-5-yl)-amide;N-(2-Methyl-1,3-benzothiazol-5-yl)-6-trifluoromethyl-nicotinamide;N-(2-Methyl-1,3-benzothiazol-5-yl)-4-propyl-benzamide;3-Iodo-N-(2-methyl-1,3-benzothiazol-5-yl)-benzamide;2,5-Dimethyl-furan-3-carboxylic acid(2-methyl-1,3-benzothiazol-5-yl)-amide;5-tert-Butyl-2-methyl-furan-3-carboxylic acid(2-methyl-1,3-benzothiazol-5-yl)-amide;4-Bromo-3-methyl-N-(2-methyl-1,3-benzothiazol-5-yl)-benzamide;3,4-Difluoro-N-(2-methyl-1,3-benzothiazol-5-yl)-benzamide;3-Chloro-2-fluoro-N-(2-methyl-1,3-benzothiazol-5-yl)-benzamide;Pyridine-2-carboxylic acid (2-methyl-1,3-benzothiazol-5-yl)-amide;2-Benzyl-5-tert-butyl-2H-pyrazole-3-carboxylic acid(2-methyl-1,3-benzothiazol-5-yl)-amide;3-Fluoro-4-trifluoromethyl-N-(2-trifluoromethyl-1H-benzimidazol-5-yl)-benzamide;2-Fluoro-5-trifluoromethyl-N-(2-trifluoromethyl-1H-benzimidazol-5-yl)-benzamide;4-Chloro-N-(2-methyl-benzothiazol-5-yl)-benzamide;1-Phenyl-5-trifluoromethyl-1H-pyrazole-3-carboxylic acid(2-methyl-1,3-benzothiazol-5-yl)-amide;1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid(2-methyl-1,3-benzothiazol-5-yl)-amide;2,3-Difluoro-N-(2-methyl-1,3-benzothiazol-5-yl)-4-trifluoromethyl-benzamide;3-Fluoro-4-methyl-N-(2-methyl-1,3-benzothiazol-5-yl)-benzamide;4-tert-Butyl-N-(2-methyl-1,3-benzothiazol-5-yl)-benzamide;4-Ethyl-N-(2-methyl-1,3-benzothiazol-5-yl)-benzamide;4-tert-Butyl-N-(2-methyl-1,3-benzooxazol-5-yl)-benzamide;Biphenyl-4-carboxylic acid (2-methyl-1,3-benzothiazol-5-yl)-amide;3-Bromo-thiophene-2-carboxylic acid(2-methyl-1,3-benzothiazol-5-yl)-amide;4-Bromo-2-methyl-N-(2-methyl-1,3-benzothiazol-5-yl)-benzamide;4-tert-Butoxy-N-(2-methyl-1,3-benzothiazol-5-yl)-benzamide;2-Chloro-3,4-dimethoxy-N-(2-methyl-1,3-benzothiazol-5-yl)-benzamide;4-Iodo-N-(2-methyl-1,3-benzothiazol-5-yl)-benzamide;4-Amino-N-(2-methyl-1,3-benzothiazol-5-yl)-3-nitro-benzamide;N-(2-Methyl-1,3-benzothiazol-5-yl)-4-vinyl-benzamide;4-Ethoxy-N-(2-methyl-1,3-benzothiazol-5-yl)-benzamide;4-Ethylsulfanyl-N-(2-methyl-1,3-benzothiazol-5-yl)-benzamide;4-Dimethylamino-naphthalene-1-carboxylic acid(2-methyl-1,3-benzothiazol-5-yl)-amide;2-Fluoro-6-iodo-N-(2-methyl-1,3-benzothiazol-5-yl)-benzamide;4-Ethoxymethyl-N-(2-methyl-1,3-benzothiazol-5-yl)-benzamide;N-(2-Methyl-1,3-benzothiazol-5-yl)-4-trifluoromethoxy-benzamide;4-Chloro-3-fluoro-N-(2-methyl-1,3-benzothiazol-5-yl)-benzamide;4-tert-Butyl-N-(2-formyl-1,3-benzothiazol-5-yl)-benzamide;4-tert-Butyl-N-(2-hydroxymethyl-1,3-benzothiazol-5-yl)-benzamide;4-tert-Butyl-N-(2-{[(2-methoxypyridin-3-yl)amino]methyl}-1,3-benzothiazol-5-yl)benzamide;4-tert-Butyl-N-[2-( 1-hydroxyethyl)-1,3-benzothiazol-5-yl]benzamide;4-tert-Butyl-N-{2-[(1H-pyrazol-3-ylamino)methyl]-1,3-benzothiazol-5-yl}benzamide;4-(1,1-Dimethylethyl)-N-[2-[[(4-nitrophenyl)amino]methyl]-5-benzothiazolyl]-benzamide;N-[2-(Aminomethyl)-1,3-benzothiazol-5-yl]-4-tert-butylbenzamide;4-tert-Butyl-N-(2-{[(methylsulfonyl)amino]methyl}-1,3-benzothiazol-5-yl)benzamide;N-{2-[(Acetylamino)methyl]-1,3-benzothiazol-5-yl}-4-tert-butylbenzamide;5-[(4-tert-Butylbenzoyl)amino]-1,3-benzothiazole-2-carboxamide;N-1,3-Benzothiazol-5-yl-4-tert-butylbenzamide;4-Chloro-N-[2-(hydroxymethyl)-1,3-benzothiazol-5-yl]benzamide;1-(4-chlorophenyl)-N-[2-(hydroxymethyl)-1,3-benzothiazol-5-yl]-5-propyl-1H-pyrazole-4carboxamide;1-(4-Chlorophenyl)-N-[2-(hydroxymethyl)-1,3-benzothiazol-5-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;N-(2,4-Dimethyl-1,3-benzothiazol-5-yl)-4-(1-hydroxy-1-methylethyl)benzamide;4-(Hydroxymethyl)-N-[2-(hydroxymethyl)-1,3-benzothiazol-5-yl]benzamide;4-tert-Butyl-N-(4-cyano-2-methyl-1,3-benzothiazol-5-yl)benzamide;4-tert-Butyl-N-[2-(hydroxymethyl)-1,3-benzoxazol-5-yl]benzamide;5-(4-tert-Butylbenzoylamino)-1,3-benzothiazol-2-ylcarboxylic acid, and4-tert-Butyl-N-(2-methoxycarbonyl-1,3-benzothiazol-5-yl)-benzamide; or asalt, solvate or solvated salt thereof, in association with one or morepharmaceutically acceptable diluents, excipients or inert carriers. 40.A method of treating VR1 mediated disorders, acute and chronic paindisorders, acute and chronic neuropathic pain or acute and chronicinflammatory pain comprising administering a therapeutically effectiveamount of a pharmaceutical composition according to claim 39.